Value through Innovation04 July 2015

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

85 publications regarding Central Nervous System
  • Author:
    Delotterie DF; Mathis C; Cassel J-C; Rosenbrock H; Dorner-Ciossek C; Marti A
    Title:
    Touchscreen tasks in mice to demonstrate differences between hippocampal and striatal functions
    Source:
    Neurobiol Learn Memory 120, 16-27 (2015)
    Abstract:
    In mammals, hippocampal and striatal regions are engaged in separable cognitive processes usually assessed through species-specific paradigms. To reconcile cognitive testing among species, translational advantages of the touchscreen-based automated method have been recently promoted. However, it remains undetermined whether similar neural substrates would be involved in such behavioral tasks both in humans and rodents. To address this question, the effects of hippocampal or dorso-striatal fiber-sparing lesions were first assessed in mice through a battery of tasks (experiment A) comprising the acquisition of two touchscreen paradigms, the Paired Associates Learning (dPAL) and Visuo-Motor Conditional Learning (VMCL) tasks, and a more classical T-maze alternation task. Additionally, we sought to determine whether post-acquisition hippocampal lesions would alter memory retrieval in the dPAL task (experiment B). Pre-training lesions of dorsal striatum caused major impairments in all paradigms. In contrast, pre-training hippocampal lesions disrupted the performance of animals trained in the T-maze assay, but spared the acquisition in touchscreen tasks. Nonetheless, post-training hippocampal lesions severely impacted the recall of the previously learned dPAL task. Altogether, our data show that, after having demonstrated their potential in genetically modified mice, touchscreens also reveal perfectly adapted to taxing functional implications of brain structures in mice by means of lesion approaches. Unlike its human counterpart requiring an intact hippocampus, the acquisition of the dPAL task requires the integrity of the dorsal striatum in mice. The hippocampus only later intervenes, when acquired information needs to be retrieved. Touchscreen assays may therefore be suited to study striatal- or hippocampal-dependent forms of learnings in mice
  • Author:
    Grozdanov V; Bliederhaeuser C; Ruf WP; Roth V; Fundel-Clemens K; Zondler L; Brenner D; Martin-Villalba A; Hengerer B; Kassubek J; Ludolph AC; Weishaupt JH; Danzer KM
    Title:
    Inflammatory dysregulation of blood monocytes in Parkinson.s disease patients
    Source:
    Acta Neuropathol 128 (5), 651-663 (2014)
    Abstract:
    Despite extensive effort on studying inflammatory processes in the CNS of Parkinson.s disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte-recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a .second hit.. These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation.
  • Author:
    Ernsting A; Knoll N; Schneider M; Schwarzer R
    Title:
    The enabling effect of social support on vaccination uptake via self-efficacy and planning
    Source:
    Psychol Health Med 20 (2), 239-246 (2015)
    Abstract:
    Purpose: In the context of worksite influenza vaccination programmes, social support, action planning and perceived self-efficacy were examined as predictors of participation. Mechanisms among these predictors were analysed by applying the enabling effect model to vaccination. Moreover, this model was extended by the inclusion of planning. Methods: In a large German company, a survey on influenza vaccination was launched with 200 employees taking part in the five-month follow-up. Using regression procedures, a sequential mediation model was examined, leading from social support via self-efficacy and planning to vaccination behaviour. Results: The three predictors jointly accounted for 47% of the vaccination participation variance. The enabling effect model was con firmed, highlighting how social support may promote self-efficacy beliefs. Further analysis yielded the extended model, revealing planning as a mediator between self-efficacy and subsequent behaviour while the indirect path from social support via self-efficacy to behaviour remained. Conclusions: Multiple step mediation analysis underscored the relevance of social support and self-efficacy. It also revealed planning as a proximal factor that may facilitate participation in a worksite influenza vaccination programme.
  • Author:
    Pasquarelli N; Porazik C; Hanselmann J; Weydt P; Ferger B; Witting A
    Title:
    Comparative biochemical characterization of the monoacylglycerol lipase inhibitor KML29 in brain, spinal cord, liver, spleen, fat and muscle tissue
    Source:
    Neuropharmacology 91, 148-156 (2015)
    Abstract:
    Monoacylglycerol lipase (MAGL) is part of the endocannabinoid and the prostaglandin signaling system. MAGL degrades the endocannabinoid 2-arachidonoylglycerol (2-AG) into glycerol and arachidonic acid. MAGL-induced arachidonic acid is the primary source for prostaglandin synthesis in the brain. 2-AG mainly induces neuroprotective and anti-inflammatory effects, whereas prostaglandins are related to pro-inflammatory effects inducing neurotoxicity. Therefore, inhibition of MAGL represents a promising target for neurological diseases characterized by inflammation. However, as 2-AG is an agonist for the cannabinoid receptor 1 (CB1), inhibition of MAGL might be associated with unwanted cannabimimetic effects. Here, we show that oral administration of KML29, a highly selective inhibitor of MAGL, induced large and dose-dependent changes in 2-AG levels in vivo in brain and spinal cord of mice. Of note, MAGL inhibition by KML29 induced a decrease in prostaglandin levels in brain and most peripheral tissues but not in the spinal cord. MAGL expression was highest in fat, liver and brain, whereas the cytosolic phospholipase A2 (cPLA2), a further enzyme responsible for arachidonic acid production, was highly expressed in spinal cord, muscle and spleen. In addition, high doses (10 mg/kg) of KML29 induced some cannabimimetic effects in vivo in the tetrad test, including hypothermia, analgesia and hypomotility without induction of cataleptic behavior. In summary, inhibition of MAGL by KML29 represents a promising strategy for targeting the cannabinoid and prostaglandin system of the brain with only a moderate induction of cannabimimetic effects.
  • Author:
    Davidai G; Cotton D; Gorelick P; Bath PMW; Lipton RB; Sacco R; Diener H-C
    Title:
    Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: A post hoc analysis
    Source:
    Eur J Neurol 21 (10), 1311-1317 (2014)
    Abstract:
    Background and purpose: Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER-DP) when administered alone or with low-dose aspirin (ASA+ER-DP). Methods: This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20 332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model. Results: In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06). Conclusions: Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function.
  • Author:
    Toni D; Di Angelantonio E; Di Mascio MT; Vinisko R; Bath PMW
    Title:
    Types of stroke recurrence in patients with ischemic stroke: A substudy from the PRoFESS trial
    Source:
    Int J Stroke 9 (7), 873-878 (2014)
    Abstract:
    Background: Risk profiles for stroke recurrence are poorly characterized. Aims: We determined the variation in the risk and type of recurrent stroke among index ischemic stroke subtypes, and whether index stroke subtype and conventional stroke risk factors were predictors of stroke recurrence. Methods: Patients enrolled in the Prevention Regimen for Effectively Avoiding Second Strokes trial were included in this study. Results: In 1794 patients' recurrent stroke subtypes were the same as the index stroke in: 48.3% of patients with large artery atherothrombosis stroke; 50% of patients with cardioembolic stroke; 48.7% of patients with small artery occlusion stroke; 8.1% of patients with stroke of other etiology, and 45.3% of patients with undetermined etiology stroke. Patients with cardioembolic stroke, who were unwilling or unable to take oral anticoagulants, had the greatest risk of stroke recurrence. Predictors of stroke recurrence in multivariable analysis were: older age and previous stroke among large artery atherothrombosis strokes; older age, male sex, previous stroke, previous transient ischemic attack, hypertension, diabetes, and tobacco use among small artery occlusion strokes; older age among cardioembolic strokes; atrial fibrillation and anti-diabetic medications among other etiology strokes; older age, previous stroke and atrial fibrillation among undetermined etiology strokes. Predictors of brain hemorrhage as recurrent stroke were index small artery occlusion stroke, older age, previous stroke, and antiplatelet treatment with aspirin plus extended-release dipyridamole. Conclusions: Risk predictors for stroke recurrence and for brain hemorrhage differ by index ischemic stroke subtype, information that is important when initiating secondary prevention therapy.
  • Author:
    Grozdanov V; Bliederhaeuser; C Ruf WP; Roth V; Fundel-Clemens K; Zondler L; Brenner D; Martin-Villalba A; Hengerer B; Kassubek J; Ludolph AC; Weishaupt JH; Danzer K
    Title:
    Inflammatory dysregulation of blood monocytes in Parkinson.s disease patients
    Source:
    Acta Neuropathol-13 Article in Press (2014)
    Abstract:
    Despite extensive effort on studying inflammatory processes in the CNS of Parkinson.s disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte-recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a .second hit.. These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation.
  • Author:
    Delotterie D
    Title:
    Translational potential of the touchscreen-based methodology in mice:focus on the Paired Associates Learning (PAL) task
    Source:
    PhD Thesis Defense, Strasbourg, France, Sep 24, 2014
  • Author:
    Wang Y; Sun S; Zhu S; Liu C; Liu Y; Di Q; Shang H; Ren Y; Lu C; Gordon MF; Juhel N; Chen S
    Title:
    The efficacy and safety of pramipexole ER versus IR in Chinese patients with Parkinson's disease: A randomized, double-blind, double-dummy, parallel-group study
    Source:
    Transl Neurodegener 3 (1) art.no.11 (2014)
    Abstract:
    Objective: To evaluate the non-inferiority of pramipexole extended-release (ER) versus immediate-release (IR) in Chinese patients with Parkinson's disease (PD) in a double-blind, randomized, parallel-group study. Methods: Subjects were Chinese patients with idiopathic PD with diagnosis . 2 years prior to trial, age . 30 years old at diagnosis, and Modified Hoehn and Yahr score 2-4 during 'on'-time. Subjects received treatment with pramipexole ER (n=234) or IR (n=239). Non-inferiority was based on the primary endpoint, the change from baseline to end of maintenance (week 18) in the UPDRS (Parts II + III) total score. Results: For the primary endpoint, the adjusted mean changes (standard error) of UPDRS Parts II + III at week 18 were -13.81 (0.655) and -13.05 (0.643) for ER and IR formulations, respectively, using ANCOVA adjusted for treatment and centre (fixed effect) and baseline (covariate). The adjusted mean between group difference was 0.8 for the 2-sided 95% CI (-1.047, 2.566). Since the lower limit of the 2-sided 95% CI (-1.047) for treatment difference was higher than the non-inferiority margin of -4, non-inferiority between pramipexole ER and IR was demonstrated. The incidence of adverse events (AEs) was 68.8% in the ER arm and 73.6% in the IR arm with few severe AEs (ER: 2.1%; IR: 3.8%). Conclusion: Based on the UPDRS II + III score, pramipexole ER was non-inferior to pramipexole IR. The safety profiles of pramipexole ER and IR were similar. These results were based on comparable mean daily doses and durations of treatment for both formulations.
  • Author:
    Demyttenaere K; Desaiah D; Raskin J; Cairns V; Brecht S
    Title:
    Suicidal thoughts and reasons for living in hospitalized patients with severe depression: Post-hoc analyses of a double-blind randomized trial of duloxetine
    Source:
    Prim Care Companion J Clin Psychiatry 16 (3) (2014)
    Abstract:
    Objective: To evaluate suicidal thoughts in relationship to depressive symptom severity and reasons for living in patients hospitalized for major depressive disorder (MDD). Method: A post hoc analysis was conducted of a randomized, double-blind, parallel-group trial involving hospitalized patients with MDD (DSM-IV criteria) who received duloxetine 60 mg once daily or duloxetine 60 mg twice daily for 8 weeks. After 4 weeks, the dose for nonresponders receiving 60 mg once daily could be increased to 60 mg twice daily (double-blind). The study was conducted between February 9, 2007, and August 26, 2008 at 43 centers in 4 countries across Europe and South Africa. Suicidal thoughts were assessed with Montgomery-Asberg Depression Rating Scale (MADRS) item 10, depression severity was assessed with the 6-item Hamilton Depression Rating Scale and the Clinical Global Impressions-Severity of Illness scale, and protective factors were assessed with the patient-rated Reasons for Living Inventory (RFL) assessing 6 domains. Descriptive statistics, correlation, and linear regression analysis were performed. Results: At baseline, patients (N = 336) had varying severity of suicidal thoughts: 18% had a score . 4. The proportion of patients with a score . 4 decreased to 7% at week 1 and 1% at week 8 of treatment. The RFL scores at baseline were lower in patients with higher baseline suicidal thoughts and increased significantly during treatment (P <.0001). A regression model revealed that only 16% of variance in baseline total RFL score is explained by the different MADRS items. Eight patients had suicidal behavior or ideation recorded as an adverse event during the study; no consistent pattern was found in the different psychometric scores either at baseline or at the visit preceding the suicidal behavior/ideation. Conclusions: Suicidality rapidly decreased in hospitalized patients with severe depression treated with duloxetine. The RFL scores were low at baseline but increased during treatment, suggesting that they are at least partially state rather than trait variables. Since RFL scores are lower in depressed inpatients, these scores lose the predictive value that they have in a general population sample. © 2014 Physicians Postgraduate Press, Inc.
  • Author:
    Davidai G; Cotton D; Gorelick P; Bath PMW; Lipton RB; Sacco R; Diener H-C
    Title:
    Dipyridamole-induced headache and lower recurrence risk in secondary prevention of ischaemic stroke: A post hoc analysis
    Source:
    Eur J Neurol Article in Press (2014)
    Abstract:
    Background and purpose: Our objective was to investigate the association between recurrent stroke risk and headache induced by extended-release dipyridamole (ER-DP) when administered alone or with low-dose aspirin (ASA+ER-DP). Methods: This was a post hoc analysis of prospectively collected data on recurrent stroke risk and headache as an adverse event or reason for treatment discontinuation from the PRoFESS (N = 20 332) and ESPS2 (N = 6602) trials. Hazard ratios (HRs) for recurrent stroke were calculated using the Cox model. Results: In PRoFESS, the 2.5-year recurrent stroke risk in patients receiving ASA+ER-DP was 8.2% in those with headache within 7 days of starting treatment and 9.4% in those without [HR 0.85, 95% confidence interval (CI) 0.73-0.98; P = 0.03]. Recurrent stroke risk was 5.0% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.2% in those who did not (HR 0.52, 95% CI 0.35-0.77; P = 0.001). No such difference was observed in clopidogrel-treated patients. In ESPS2, risk of recurrent stroke was 6.2% in patients who discontinued ASA+ER-DP due to headache by day 90 versus 9.8% in patients who did not (HR 0.62, 95% CI 0.31-1.27; P = 0.19) and 7.3% in patients who discontinued ER-DP due to headache by day 90 versus 13.2% in those who did not (HR 0.53, 95% CI 0.27-1.04; P = 0.06). Conclusions: Patients taking ASA+ER-DP in PRoFESS who developed headache had significantly reduced stroke recurrence risk versus those without headache. Similar (non-significant) findings for ASA+ER-DP and ER-DP in ESPS2 suggest that dipyridamole-induced headache may reflect better cerebrovascular function. © 2014 The Authors.
  • Author:
    Ortner NJ; Bock G; Vandael DHF; Mauersberger R; Draheim HJ; Gust R; Carbone E; Tuluc P; Striessnig J
    Title:
    Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca 2+ channel activators
    Source:
    Nat Commun 5 art.no.3897 (2014)
    Abstract:
    Cav1.2 and Cav1.3 are the main L-type Ca2+ channel subtypes in the brain. Cav1.3 channels have recently been implicated in the pathogenesis of Parkinsonâ .. s disease. Therefore, Cav1.3-selective blockers are developed as promising neuroprotective drugs. We studied the pharmacological properties of a pyrimidine-2,4,6-trione derivative (1-(3-chlorophenethyl)-3- cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione, Cp8) recently reported as the first highly selective Cav1.3 blocker. Here we show, in contrast to this previous study, that Cp8 reproducibly increases inward Ca2+ currents of Cav1.3 and Cav1.2 channels expressed in tsA-201 cells by slowing activation, inactivation and enhancement of tail currents. Similar effects are also observed for native Cav1.3 and Cav1.2 channels in mouse chromaffin cells, while non-L-type currents are unaffected. Evidence for a weak and non-selective inhibition of Cav1.3 and Cav1.2 currents is only observed in a minority of cells using Ba2+ as charge carrier. Therefore, our data identify pyrimidine-2,4,6-triones as Ca2+ channel activators. © 2014 Macmillan Publishers Limited. All rights reserved.
  • Author:
    Delotterie D; Mathis C; Cassel J-C; Dorner-Ciossek C; Marti A
    Title:
    Optimization of touchscreen-based behavioral paradigms in mice: Implications for building a battery of tasks taxing learning and memory functions
    Source:
    PloS ONE 9 (6) art.no.e100817 (2014)
    Abstract:
    Although many clinical pathological states are now detectable using imaging and biochemical analyses, neuropsychological tests are often considered as valuable complementary approaches to confirm diagnosis, especially for disorders like Alzheimer's or Parkinson's disease, and schizophrenia. The touchscreen-based automated test battery, which was introduced two decades ago in humans to assess cognitive functions, has recently been successfully back-translated in monkeys and rodents. We focused on optimizing the protocol of three distinct behavioral paradigms in mice: two variants of the Paired Associates Learning (PAL) and the Visuo-Motor Conditional Learning (VMCL) tasks. Acquisition of these tasks was assessed in naive versus pre-trained mice. In naive mice, we managed to define testing conditions allowing significant improvements of learning performances over time in the three aforementioned tasks. In pre-trained mice, we observed differential acquisition rates after specific task combinations. Particularly, we identified that animals previously trained in the VMCL paradigm subsequently poorly learned the sPAL rule. Together with previous findings, these data confirm the feasibility of using such behavioral assays to evaluate the power of different models of cognitive dysfunction in mice. They also highlight the risk of interactions between tasks when rodents are run through a battery of different cognitive touchscreen paradigms. © 2014 Delotterie et al.
  • Author:
    Höllerhage M; Goebel JN; de Andrade A; Hildebrandt T; Dolga A; Culmsee C; Oertel WH; Hengerer B; Höglinger GU
    Title:
    Trifluoperazine rescues human dopaminergic cells from wild-type alpha-synuclein-induced toxicity
    Source:
    Neurobiol Aging 35 (7), 1700-1711 (2014)
    Abstract:
    Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species. © 2014 Elsevier Inc.
  • Author:
    Kroker KS; Mathis C; Marti A C; assel J-C; Rosenbrock H; Dorner-Ciossek C
    Title:
    PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition
    Source:
    Neurobiol Aging 35 (9), 2072-2078 (2014)
    Abstract:
    The cyclic nucleotide cGMP is an important intracellular messenger for synaptic plasticity and memory function in rodents. Therefore, inhibition of cGMP degrading phosphodiesterases, like PDE9A, has gained interest as potential target for treatment of cognition deficits in indications like Alzheimer's disease (AD). In fact, PDE9A inhibition results in increased hippocampal long-term potentiation and exhibits procognitive effects in rodents. To date, however, no evidence has been published linking PDE9A inhibition to the pathologic hallmarks of AD such as amyloid beta (A.) deposition. Therefore, we investigated the role of PDE9A inhibition in an AD relevant context by testing its effects on A.-related deficits in synaptic plasticity and cognition. The PDE9A inhibitor BAY 73-6691 was found to restore long-term potentiation impaired by A.42 oligomers. Furthermore, we demonstrated that BAY 73-6691 enhanced cGMP levels in the hippocampus of APP transgenic tg2576 mice and improved memory performance of these mice. Altogether, our results support the hypothesis that inhibition of PDE9A could be a beneficial approach for the treatment of memory impairment in AD patients. © 2014 Elsevier Inc.
  • Author:
    Powrózek T; Krawczyk P; Jarosz B; Mlak R; Wojas-Krawczyk K; Sawicki M; Stencel D; Trojanowski T; Milanowski J
    Title:
    The Application of Real-Time PCR Technique to Detect Rare Cell Clones with Primary T790M Substitution of EGFR Gene in Metastases of Non-small Cell Lung Cancer to Central Nervous System in Chemotherapy Naive Patients
    Source:
    Pathol Oncol Res Article in Press (2014)
    Abstract:
    The time-limited efficacy of reversible EGFR-TKIs in patients with advanced non-small cell lung cancer (NSCLC) with EGFR gene activating mutations is associated with development of treatment resistance after some period of therapy. This resistance predominantly results from secondary mutations located in EGFR gene, especially T790M substitution. There is limited information available concerning the prevalence of primary T790M mutations in patients with metastatic NSCLC tumors before treatment with EGFR-TKIs. The aim of work was to assess the prevalence of de novo T790M mutations in EGFR gene in tissue samples from NSCLC metastatases in central nervous system (CNS) in both chemotherapy and EGFR-TKI naive NSCLC patients. We analyzed DNA samples isolated from paraffin-embedded tissue from CNS metastases for T790M mutations using real-time PCR and TaqMan probe against the T790M mutant sequence. The tissue samples were taken during palliative neurosurgery in 143 NSCLC patients. Amplification of the T790M-specific sequence was detected in 25 patients (17.5 %). The quantity of mutated DNA was less than 1 % in all samples with amplification, and in vast majority (20 patients, 14 % of all samples) it was even less that 0.1 %. In 5 patients (3.5 %) quantity of mutated DNA ranged from 0.1 to 1 % and true positive results of T790M mutation presence in these patients were most possible. Amplification of this sequence was not concurrent with common EGFR mutations and was not associated with sex, smoking status and pathological type of cancer. There is a possibility to detect the primary T790M mutation in brain metastases of NSCLC in EGFR-TKIs naïve patients. © 2014 The Author(s).
  • Author:
    Ernsting A; Knoll N; Schneider M; Schwarzer R
    Title:
    The enabling effect of social support on vaccination uptake via self-efficacy and planning
    Source:
    Psychol Health Med Articl in Press (2014)
    Abstract:
    Purpose: In the context of worksite influenza vaccination programmes, social support, action planning and perceived self-efficacy were examined as predictors of participation. Mechanisms among these predictors were analysed by applying the enabling effect model to vaccination. Moreover, this model was extended by the inclusion of planning. Methods: In a large German company, a survey on influenza vaccination was launched with 200 employees taking part in the five-month follow-up. Using regression procedures, a sequential mediation model was examined, leading from social support via self-efficacy and planning to vaccination behaviour. Results: The three predictors jointly accounted for 47% of the vaccination participation variance. The enabling effect model was confirmed, highlighting how social support may promote self-efficacy beliefs. Further analysis yielded the extended model, revealing planning as a mediator between self-efficacy and subsequent behaviour while the indirect path from social support via self-efficacy to behaviour remained. Conclusions: Multiple step mediation analysis underscored the relevance of social support and self-efficacy. It also revealed planning as a proximal factor that may facilitate participation in a worksite influenza vaccination programme. © 2014 © 2014 Taylor & Francis.
  • Author:
    Gorham L; Just S; Doods H
    Title:
    Somatostatin 4 receptor activation modulates TPRV1 currents in dorsal root ganglion neurons
    Source:
    Neurosci Lett 573, 35-39 (2014)
    Abstract:
    Somatostatin (sst) is a cyclic neuropeptide known to have inhibitory roles in the central nervous system. It exerts its biological effects via the activation of the 5 sst receptor subtypes, which belong to the family of G-protein coupled receptors (GPCR). This peptide has analgesic properties, specifically via the activation of the sst4 receptor subtype. Although this is established, the precise molecular mechanisms causing this have not yet been fully elucidated. This research aimed to identify a possible anti-nociceptive mechanism, showing functional links to the transient receptor potential vanilloid type 1 (TRPV1) within the pain processing pathway. Calcium imaging and whole cell voltage clamp experiments were conducted on DRG neurons prepared from adult rats, utilizing capsaicin stimulations and the sst4 receptor specific agonist J-2156. The complete Freund's adjuvant (CFA) inflammatory pain model was used to examine if effects are augmented in pain conditions. The sst4 receptor agonist J-2156 was able significantly to inhibit capsaicin induced calcium and sodium influx, where the effect was more potent after CFA treatment. This inhibition identifies a contributory molecular mechanism to the analgesic properties of sst4 receptor activation. © 2014 Elsevier Ireland Ltd.
  • Author:
    Caesar M; Felk S; Zach S; Brønstad G; Aasly JO; Gasser T; Gillardon F
    Title:
    Changes in matrix metalloprotease activity and progranulin levels may contribute to the pathophysiological function of mutant leucine-rich repeat kinase 2
    Source:
    GLIA 62 (7), 1075-1092 (2014)
    Abstract:
    Increasing evidence suggests that Parkinson's disease (PD)-linked Leucine-rich repeat kinase 2 (LRRK2) has a role in peripheral and brain-resident immune cells. Furthermore, dysregulation of the anti-inflammatory, neurotrophic protein progranulin (PGRN) has been demonstrated in several chronic neurodegenerative diseases. Here we show that PGRN levels are significantly reduced in conditioned medium of LRRK2(R1441G) mutant mouse fibroblasts, leukocytes, and microglia, whereas levels of proinflammatory factors, like interleukin-1. and keratinocyte-derived chemokine, were significantly increased. Decreased PGRN levels were also detected in supernatants of cultured human fibroblasts isolated from presymptomatic LRRK2(G2019S) mutation carriers, while mitochondrial function was unaffected. Furthermore, medium levels of matrix metalloprotease (MMP) 2 increased, whereas MMP 9 decreased in LRRK2(R1441G) mutant microglia. Increased proteolytic cleavage of the MMP substrates ICAM-5 and .-synuclein in synaptoneurosomes from LRRK2(R1441G) mutant mouse brain indicates increased net synaptic MMP activity. PGRN levels were decreased in the cerebrospinal fluid of presymptomatic LRRK2 mutant mice, whereas PGRN levels were increased in aged symptomatic mutant mice. Notably, PGRN levels were also increased in the cerebrospinal fluid of PD patients carrying LRRK2 mutations, but not in idiopathic PD patients and in healthy control donors. Our data suggest that proinflammatory activity of peripheral and brain-resident immune cells may particularly contribute to the early stages of Parkinson's disease caused by LRRK2 mutations. © 2014 Wiley Periodicals, Inc.
  • Author:
    Gillardon F
    Title:
    Cyclin-dependent kinase 5: A target for neuroprotection?
    Source:
    Apoptosis 2, 81-100 (2014)
    Abstract:
    Cyclin-dependent kinase 5 (CDK5) activity is mainly restricted to the nervous system where it plays a central role in neuronal development and neurotransmission. There is increasing evidence that overactivation of CDK5 contributes to the pathogenesis of both chronic and acute neurodegenerative diseases suggesting that deregulated CDK5 may represent a therapeutic target for neuroprotection. By high-throughput screening we identified small molecule CDK5 inhibitors that prevented neuronal cell death in various paradigms. The compounds blocked the cell death program upstream of mitochondrial depolarization and cytochrome c release. Phosphoproteome analysis revealed potential mechanisms underlying neuroprotection by CDK5 inhibitors, but also indicated interference with the physiological function of CDK5. Microarray analysis demonstrated rapid changes in gene expression following administration of CDK5 inhibitors to cultured neurons. Although compound-related effects cannot be excluded, our data advise caution when considering CDK5 inhibitors as therapeutic agents in chronic neurodegenerative diseases. © 2007 Humana Press Inc. All rights reserved.
  • Author:
    Oeckl P; Hengerer B; Ferger B
    Title:
    G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson's disease
    Source:
    Exp Neurol 257, 1-9 (2014)
    Abstract:
    The orphan G-protein coupled receptor 6 (GPR6) is a constitutively active receptor which is positively coupled to the formation of cyclic adenosine-3',5'-monophosphate (cAMP). GPR6 is predominantly expressed in striatopallidal neurons. Here, we investigated neurochemical and behavioural effects of Gpr6 deficiency in mice.Gpr6 depletion decreased in vivo cAMP tissue concentrations (20%) in the striatum. An increase of striatal tissue dopamine concentrations (10%) was found in Gpr6-/- mice, whereas basal extracellular dopamine levels were not changed compared with Gpr6+/+ mice, as shown by in vivo microdialysis. Western blot analyses revealed no alteration in the expression and subcellular localisation of the dopamine D2 receptor in the striatum of Gpr6-/- mice, and the number of tyrosine hydroxylase positive neurons in the substantia nigra was unchanged. DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32kDa) expression in the striatum of Gpr6-/- mice was not altered, however, a twofold increase in the phosphorylation of DARPP-32 at Thr34 was detected in Gpr6-/- compared with Gpr6+/+ mice. Gpr6-/- mice showed higher locomotor activity in the open field, which persisted after treatment with the dopamine D2 receptor antagonist haloperidol. They also displayed reduced abnormal involuntary movements after apomorphine and quinpirole treatment in the mouse dyskinesia model of Parkinson's disease. In conclusion, the depletion of Gpr6 reduces cAMP concentrations in the striatum and alters the striatal dopaminergic system. Gpr6 deficiency causes an interesting behavioural phenotype in the form of enhanced motor activity combined with reduced abnormal involuntary movements. These findings could offer an opportunity for the treatment of Parkinson's disease beyond dopamine replacement. © 2014 Elsevier Inc.
  • Author:
    Karaca E; Weitzer S; Pehlivan D; Shiraishi H; Gogakos T; Hanada T; Jhangiani SN; Wiszniewski W; Withers M; Campbell IM; Erdin S; Isikay S; Franco LM; Gonzaga-Jauregui C; Gambin T; Gelowani V; Hunter JV; Yesil G; Koparir E; Yilmaz S; Brown M; Briskin D; Hafner M; Morozov P; Farazi TA; Bernreuther C; Glatzel M; Trattnig S; Friske J; Kronnerwetter C; Bainbridge MN; Gezdirici A; Seven M; Muzny DM; Boerwinkle E; Ozen M; Clausen T; Tuschl T; Yuksel A; Hess A; Gibbs RA; Martinez J; Penninger JM; Lupski JR
    Title:
    Human CLP1 mutations alter tRNA biogenesis, Affecting both peripheral and central nervous system function
    Source:
    Cell 157 (3), 636-650 (2014)
    Abstract:
    CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis. © 2014 Elsevier Inc.
  • Author:
    Rosenbrock H; Kroker K; Bertani B; Stierstorfer B; Dorner-Ciossek C; Arban R
    Title:
    Pre-synaptic localization of PDE2 enzyme and pharmacological characterization of the PDE2 inhibitor PF-999 in models related to cognitive symptoms of schizophrenia
    Source:
    4th Biennial Schizophrenia International Research Conference, Florence, Italy, Apr 5-9, 2014
  • Author:
    Kroker KS; Mathis C; Marti A; Cassel J-C; Rosenbrock H; Dorner-Ciossek C
    Title:
    PDE9A inhibition rescues amyloid beta-induced deficits in synaptic plasticity and cognition
    Source:
    Neurobiol Aging Article in Press (2014)
    Abstract:
    The cyclic nucleotide cGMP is an important intracellular messenger for synaptic plasticity and memory function in rodents. Therefore, inhibition of cGMP degrading phosphodiesterases, like PDE9A, has gained interest as potential target for treatment of cognition deficits in indications like Alzheimer's disease (AD). In fact, PDE9A inhibition results in increased hippocampal long-term potentiation and exhibits procognitive effects in rodents. To date, however, no evidence has been published linking PDE9A inhibition to the pathologic hallmarks of AD such as amyloid beta (A.) deposition. Therefore, we investigated the role of PDE9A inhibition in an AD relevant context by testing its effects on A.-related deficits in synaptic plasticity and cognition. The PDE9A inhibitor BAY 73-6691 was found to restore long-term potentiation impaired by A.42 oligomers. Furthermore, we demonstrated that BAY 73-6691 enhanced cGMP levels in the hippocampus of APP transgenic tg2576 mice and improved memory performance of these mice. Altogether, our results support the hypothesis that inhibition of PDE9A could be a beneficial approach for the treatment of memory impairment in AD patients. © 2014 Elsevier Inc. All rights reserved.
  • Author:
    Hauser RA; Schapira AHV; Barone P; Mizuno Y; Rascol O; Busse M; Debieuvre C; Fraessdorf M; Poewe W
    Title:
    Long-term safety and sustained efficacy of extended-release pramipexole in early and advanced Parkinson's disease
    Source:
    Eur J Neurol 21 (5), 736-743 (2014)
    Abstract:
    Background and purpose: To assess the long-term safety and efficacy of pramipexole as a once-daily (q.d.) extended-release oral formulation in early or advanced Parkinson's disease (PD). Methods: In two double-blind (DB) studies of early PD and one of advanced PD, active-treatment arms received pramipexole immediate release (IR) or extended release (ER), with exposure lasting up to 33 weeks. In open-label (OL) extensions that followed immediately, subjects took ER q.d. for up to 80 weeks, with dosage adjustment permitted (range 0.375-4.5 mg q.d.). Results: Of 590 subjects completing an early-PD DB study, 511 entered the early-PD OL extension; 408 completed it. Reported adverse events (AEs) with incidence .10.0% were somnolence (15.1%), peripheral edema (11.7%) and back pain (10.6%). Of 465 subjects completing the advanced-PD DB study, 391 entered the advanced-PD OL extension; 329 completed it. Reported AEs with incidence .10.0% were dyskinesia (27.4%) and somnolence (13.6%). Impulse control disorders were identified by semi-structured interview in 13 subjects (1.4% of 902). In exploratory analyses, adjusted mean Unified Parkinson's Disease Rating Scale (UPDRS) Parts II + III scores (excluding ex-placebo recipients) remained substantially improved from DB baseline scores prior to pramipexole introduction, at -6.6 and -6.3 points amongst ex-DB-ER and ex-DB-IR recipients after 113 weeks of pramipexole (33 DB plus 80 OL) in early PD, and -11.5 and -9.1 after up to 113 weeks (up to 33 DB plus 80 OL) in advanced PD. Conclusions: These results support the long-term safety and efficacy of pramipexole ER in early and advanced PD. AEs were typical for dopaminergic medications, and UPDRS scores suggested sustained symptomatic benefit. © 2014 The Author(s) European Journal of Neurology © 2014 EFNS.
  • Author:
    Höllerhage M; Goebel JN; de Andrade A; Hildebrandt T; Dolga A; Culmsee C; Oertel WH; Hengerer B; Höglinger GU
    Title:
    Trifluoperazine rescues human dopaminergic cells from wild-type alpha-synuclein-induced toxicity
    Source:
    Neurobiol Aging 35 (7), 1700-1711 (2014)
    Abstract:
    Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species. © 2014 Elsevier Inc.
  • Author:
    Kritzinger A; Ciossek T; Ferger B; Kochanek S
    Title:
    Development of a LRRK2 in vivo Parkinson Model by stereotactic intracranial injection of high-capacity adenoviral vectors
    Source:
    Meeting der Deutschen Gesellschaft für Gentherapie e.V. in Ulm, Germany, Mar 20-22, 2014
  • Author:
    Hirsch SJ; Dickenson AH
    Title:
    Morphine sensitivity of spinal neurons in the chronic constriction injury neuropathic rat pain model
    Source:
    Neurosci Lett 562, 97-101 (2014)
    Abstract:
    no Abstract available
  • Author:
    Thomas AA; Hunt KW; Volgraf M; Watts RJ; Liu X; Vigers G; Smith D; Sammond D; Tang TP; Rhodes SP; Metcalf AT; Brown KD; Otten JN; Burkard M; Cox AA; Do MKG; Dutcher D; Rana S; Delisle RK; Regal K; Wright AD; Groneberg R; Scearce-Levie K; Siu M; Purkey HE; Lyssikatos JP; Gunawardana IW
    Title:
    Discovery of 7-tetrahydropyran-2-yl chromans:beta-site amyloid precursorprotein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid beta-protein (alpha beta) in the central nervous system
    Source:
    J Med Chem 57 (3), 878-902 (2014)
    Abstract:
    In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2. sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring A.1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (C free,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of A.1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62. © 2014 American Chemical Society.
  • Author:
    Höllerhage M; Goebel JN; de Andrade A; Hildebrandt T; Dolga A; Culmsee C; Oertel WH; Hengerer B; Höglinger GU
    Title:
    Trifluoperazine rescues human dopaminergic cells from wild-type alpha-synuclein-induced toxicity
    Abstract:
    Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species. © 2014 Elsevier Inc. All rights reserved.
  • Author:
    Kegler K; Imbschweiler I; Ulrich R; Kovermann P; Fahlke C; Deschl U; Kalkuhl A; Baumgärnter W; Wewetzer K
    Title:
    CNS Schwann cells display oligodendrocyte precursor-like potassium channel activation and antigenic expression in vitro
    Source:
    J Neural Transm, 1-13 Article in Press (2014)
    Abstract:
    Central nervous system (CNS) injury triggers production of myelinating Schwann cells from endogenous oligodendrocyte precursors (OLPs). These CNS Schwann cells may be attractive candidates for novel therapeutic strategies aiming to promote endogenous CNS repair. However, CNS Schwann cells have been so far mainly characterized in situ regarding morphology and marker expression, and it has remained enigmatic whether they display functional properties distinct from peripheral nervous system (PNS) Schwann cells. Potassium channels (K+) have been implicated in progenitor and glial cell proliferation after injury and may, therefore, represent a suitable pharmacological target. In the present study, we focused on the function and expression of voltage-gated K+ channels Kv1-12 and accessory .-subunits in purified adult canine CNS and PNS Schwann cell cultures using electrophysiology and microarray analysis and characterized their antigenic phenotype. We show here that K+ channels differed significantly in both cell types. While CNS Schwann cells displayed prominent KD-mediated K+ currents, PNS Schwann cells elicited KD- and KA-type K+ currents. Inhibition of K+ currents by TEA and Ba2+ was more effective in CNS Schwann cells. These functional differences were not paralleled by differential mRNA expression of Kv1-12 and accessory .-subunits. However, O4/A2B5 and GFAP expressions were significantly higher and lower, respectively, in CNS than in PNS Schwann cells. Taken together, this is the first evidence that CNS Schwann cells display specific properties not shared by their peripheral counterpart. Both Kv currents and increased O4/A2B5 expression were reminiscent of OLPs suggesting that CNS Schwann cells retain OLP features during maturation. © 2014 Springer-Verlag Wien.
  • Author:
    Hauser RA; Schapira AHV; Barone P; Mizuno Y; Rascol O; Busse M; Debieuvre C; Fraessdorf M; Poewe W
    Title:
    Long-term safety and sustained efficacy of extended-release pramipexole in early and advanced Parkinson's disease
    Source:
    Eur J Neurol Article in Press (2014)
    Abstract:
    Background and purpose: To assess the long-term safety and efficacy of pramipexole as a once-daily (q.d.) extended-release oral formulation in early or advanced Parkinson's disease (PD). Methods: In two double-blind (DB) studies of early PD and one of advanced PD, active-treatment arms received pramipexole immediate release (IR) or extended release (ER), with exposure lasting up to 33 weeks. In open-label (OL) extensions that followed immediately, subjects took ER q.d. for up to 80 weeks, with dosage adjustment permitted (range 0.375-4.5 mg q.d.). Results: Of 590 subjects completing an early-PD DB study, 511 entered the early-PD OL extension; 408 completed it. Reported adverse events (AEs) with incidence .10.0% were somnolence (15.1%), peripheral edema (11.7%) and back pain (10.6%). Of 465 subjects completing the advanced-PD DB study, 391 entered the advanced-PD OL extension; 329 completed it. Reported AEs with incidence .10.0% were dyskinesia (27.4%) and somnolence (13.6%). Impulse control disorders were identified by semi-structured interview in 13 subjects (1.4% of 902). In exploratory analyses, adjusted mean Unified Parkinson's Disease Rating Scale (UPDRS) Parts II + III scores (excluding ex-placebo recipients) remained substantially improved from DB baseline scores prior to pramipexole introduction, at -6.6 and -6.3 points amongst ex-DB-ER and ex-DB-IR recipients after 113 weeks of pramipexole (33 DB plus 80 OL) in early PD, and -11.5 and -9.1 after up to 113 weeks (up to 33 DB plus 80 OL) in advanced PD. Conclusions: These results support the long-term safety and efficacy of pramipexole ER in early and advanced PD. AEs were typical for dopaminergic medications, and UPDRS scores suggested sustained symptomatic benefit. © 2014 EFNS
  • Author:
    Haertler S
    Title:
    Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6
    Source:
    Drug Metab Drug Interact 28 (4), 209-216 (2013)
    Abstract:
    The cytochrome P450 2D6 (CYP2D6) belongs to a group of CYPs considered of utmost importance in the metabolism of xenobiotics. Despite being of only minor abundance in the liver, it is involved in the clearance of > 25% of marketed drugs. Accordingly, CYP2D6 can be very efficiently inhibited by a couple of commonly used drugs such as some antidepressants, although induction by any drug has not been observed thus far. CYP2D6 was also one of the first enzymes for which a highly polymorphic expression could be shown leading to a widespread range of functionality, from a complete lack of a functional enzyme to overexpression due to multiplication of active alleles. A clear relationship between the CYP2D6 genotype and adverse events during treatment with CNSactive drugs such as codeine, antidepressants, or antipsychotics could be demonstrated. More recently, some new aspects emerged about the potential endogenous function of CYP2D6 in terms of behavior and brain disorders.
  • Author:
    Tinazzi M; Abbruzzese G; Antonini A; Ceravolo R; Fabbrini G; Lessi P; Barone P
    Title:
    Reasons driving treatment modification in Parkinson's disease: Results from the cross-sectional phase of the REASON study
    Source:
    Parkinsonism Relat Disord 19 (12), 1130-1135 (2013)
    Abstract:
    Objectives: To assess the association between clinical and socio-demographic features and anti-Parkinson drug (APD) treatment modifications in patients with PD and to describe neurologist and patient opinions regarding the need for changes in APD therapy. Methods: Subjects with PD with stable APD treatment over .3 months prior to baseline were enrolled and evaluated for socio-demographic data, disability, disease severity and neurologist and patient views on the need to modify APD treatment. Results: 775 Patients were included, 51% with Hoehn and Yahr (HY) stage 1-2 (early PD) and 49% with HY stage 2.5-4 (advanced PD). Neurologists modified APD treatment in 255 patients, 97 (25%) early PD and 158 (41%; p<0.0001) advanced PD. APD modification was strongly associated with a low educational level and UPDRS part IV score. The most common reasons behind the APD therapy changes among neurologists were presence/worsening of motor or non-motor symptoms (88% and 37% of subjects respectively). Out of 216 patients, 92% and 51% were willing to undergo APD changes to therapy because of the presence/worsening of motor or non-motor symptoms. Conclusions: Neurologist decision to change APD therapy and patients reasons for dissatisfaction with it can be prevalently attributed to the presence/worsening of motor symptoms and motor fluctuations in the advanced stages. Non-motor symptoms were considered more often by patients. The patient educational level played a key role in treatment decision. © 2013 Elsevier Ltd.
  • Author:
    Udvardi PT; Nespoli E; Rizzo F; Hengerer B; Ludolph AG
    Title:
    Nondopaminergic neurotransmission in the pathophysiology of tourette syndrome
    Source:
    Int Rev Neurobiol 112, 95-130 (2013)
    Abstract:
    A major pathophysiological role for the dopaminergic system in Tourette's syndrome (TS) has been presumed ever since the discovery that dopamine-receptor antagonists can alleviate tics. Especially recent molecular genetic studies, functional imaging studies, and some rare postmortem studies have given more and more hints that other neurotransmitter systems are involved as well. Dysfunction in the dopamine metabolism-in particular during early development-might lead to counter-regulations in the other systems or vice versa. This chapter will give an overview of the studies that prove the involvement of other neurotransmitter systems such as the major monoaminergic neurotransmitters norepinephrine, serotonin, and histamine; the most important excitatory neurotransmitter, the amino acid glutamate; the major inhibitory neurotransmitter y-aminobutyric acid, as well as acetylcholine, endocannabinoid, corticoid; and others. These studies will hopefully lead to fundamental advances in the psychopharmacological treatment of TS. While tic disorders have been previously treated mainly with dopamine antagonists, some authors already favor alpha-agonists. Clinical trials with glutamate agonists and antagonists and compounds influencing the histaminergic system are currently being conducted. Since the different neurotransmitter systems consist of several receptor subtypes which might mediate different effects on locomotor activity, patients with TS may respond differentially to selective agonists or antagonists. Effects of agonistic or antagonistic compounds on tic symptoms might also be dose dependent. Further studies will lead to a broader spectrum of psychopharmacological treatment options in TS. © 2013 Elsevier Inc.
  • Author:
    Schülert N; Just S; Corradini L; Külzer R; Bernlöhr C; Doods C
    Title:
    The bradykinin B1 receptor antagonist BI113823 reverses hyperalgesia by reducing mechanosensitivity of peripheral afferents and nociceptive-specific spinal neruons in a model of inflammtory pain
    Source:
    Schmerzkongress Hamburg 2013
  • Author:
    Fabbrini G; Abbruzzese G; Barone P; Antonini A; Tinazzi M; Castegnaro G; Rizzoli S; Morisky DE; Lessi P; Ceravolo R
    Title:
    Adherence to anti-Parkinson drug therapy in the "rEASON" sample of Italian patients with Parkinson's disease: The linguistic validation of the Italian version of the "morisky Medical Adherence scale-8 items"
    Source:
    Neurol Sci 34 (11), 2015-2022 (2013)
    Abstract:
    Information about patients' adherence to therapy represents a primary issue in Parkinson's disease (PD) management. To perform the linguistic validation of the Italian version of the self-rated 8-Item Morisky Medical Adherence Scale (MMAS-8) and to describe in a sample of Italian patients affected by PD the adherence to anti-Parkinson drug therapy and the association between adherence and some socio-demographic and clinical features. MMAS-8 was translated into Italian language by two independent Italian mother-tongue translators. The consensus version was then back-translated by an English mother-tongue translator. This translation process was followed by a consensus meeting between the authors of translation and investigators and then by two comprehension tests. The translated version of the MMAS-8 scale was then administered at the baseline visit of the "REASON" study (Italian Study on the Therapy Management in Parkinson's disease: Motor, Non-Motor, Adherence and Quality Of Life Factors) in a large sample of PD patients. The final version of the MMAS-8 was easily understood. Mean ± SD MMAS-8 score was 6.1 ± 1.2. There were no differences in adherence to therapy in relationship to disease severity, gender, educational level or decision to change therapy. The Italian version of MMAS-8, the key tool of the REASON study to assess the adherence to therapy, has shown to be understandable to patients with PD. Patients enrolled in the REASON study showed medium therapy adherence. © 2013 Springer-Verlag Italia.
  • Author:
    Ovbiagele B; Bath PM; Cotton D; Sha N; Diener H-C
    Title:
    Low glomerular filtration rate, recurrent stroke risk, and effect of renin-angiotensin system modulation
    Source:
    Stroke 44 (11), 3223-3225 (2013)
    Abstract:
    Background and Purpose: To investigate the association of low estimated glomerular filtration rate (eGFR) <60 mL/min with recurrent stroke risk and to evaluate whether add-on renin-angiotensin system modulator therapy is associated with lower recurrent stroke risk in patients with low eGFR. Methods: We analyzed the database of a multicenter trial involving 18 666 patients with recent ischemic stroke followed for 2.5 years. Primary outcome was time to first recurrent stroke. Independent associations of low eGFR with outcome in the entire cohort and add-on telmisartan treatment with outcome among those with low eGFR were evaluated. Results: Low eGFR was observed in 3630 (20.1%) patients. Patients with low eGFR were older, more likely women, with a known history of hypertension. In unadjusted analyses, patients with low eGFR were more likely to experience a recurrent stroke (hazard ratio, 1.34;95% confidence interval, 1.20-1.49). After adjusting for confounders, low eGFR was still associated with recurrent stroke but to a lesser extent (hazard ratio, 1.16;95% confidence interval, 1.04-1.31). Telmisartan treatment among patients with low eGFR was not independently associated with recurrent stroke (hazard ratio, 1.08;95% confidence interval, 0.89-1.31). Conclusions: Low eGFR is independently associated with a higher risk of recurrent stroke, but short-term add-on telmisartan therapy does not seem to mitigate this risk. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153062. © 2013 American Heart Association, Inc.
  • Author:
    Hamdam J; Sethu S; Smith T; Alfirevic A; Alhaidari M; Atkinson J; Ayala M; Box H; Cross M; Delaunois A; Dermody A; Govindappa K; Guillon J-M; Jenkins R; Kenna G; Lemmer B; Meecham K; Olayanju A; Pestel S; Rothfuss A; Sidaway J; Sison-Young R; Smith E; Stebbings R; Tingle Y; Valentin J-P; Williams A; Williams D; Park K; Goldring C
    Title:
    Safety pharmacology - Current and emerging concepts
    Source:
    Toxicol Appl Pharmacol 273 (2), 229-241 (2013)
    Abstract:
    Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. © 2013 Elsevier Inc.
  • Author:
    Fiedorowicz JG; Potash JB; Cobb B; Cavanaugh J; Solomon DA; Akhter A; Zhang T; Coryell WH
    Title:
    Response to 'Do the symptoms of bipolar disorder really show seasonal variation?'
    Source:
    Bipolar Disord 15 (7), 811-812 (2013)
  • Author:
    Stephenson D; Aviles E; Bain LJ; Brumfield M; Carrillo M; Comery TA; Compton C; Corrigan B; Gordon MF; Jack Jr CR; Katz R; Logovinsky V; Satlin A; Marek K; Nicholas T; Polhamus D; Angersbach BS; Raghavan N; Romano G; Romero K; Shaw L; Woodcock J; Vradenburg G; Isaac M
    Title:
    Coalition Against Major Diseases: Precompetitive Collaborations and Regulatory Paths to Accelerating Drug Development for Neurodegenerative Diseases
    Source:
    Ther Innov Regul Sci 47 (6), 632-638 (2013)
    Abstract:
    Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD's annual conference and discusses the key themes that are being advanced by the Critical Path Institute. © The Author(s) 2013.
  • Author:
    Speidel A; Zach S; Hengerer B; Gillardon F
    Title:
    Neuronal and glial cell culture models for studying pathological mechanisms of Parkinson's Disease associated LRRK2 mutations
    Source:
    International Graduate School in Molecular Medicine Ulm, Fall meeting 2013, First Intermediate Exam
  • Author:
    Hirsch S; Dickenson T; Corradini L
    Title:
    Neuronal Activity and Drug Profiles in neuropathic pain models is influenced by anaesthesia rather tahnnerve injury methodology
    Source:
    EFIC, Florence, Italy, Oct 9-12, 2013
  • Author:
    Fiedorowicz JG; Potash JB; Cobb B; Cavanaugh J; Solomon DA; Akhter A; Zhang T; Coryell WH
    Title:
    Response to 'Do the symptoms of bipolar disorder really show seasonal variation?
    Source:
    Bipolar Disord Article in Press (2013)
    Abstract:
    no abstract available
  • Author:
    Mar J; Álvarez-Sabín J; Oliva J; Becerra V; Casado M; Yébenes M; González-Rojas N; Arenillas JF; Martínez-Zabaleta MT; Rebollo M; Lago A; Segura T; Castillo J; Gállego J; Jiménez-Martínez C; López-Gastón JI; Moniche F; Casado-Naranjo I; López-Fernández JC; González-Rodríguez C; Escribano B; Masjuan J
    Title:
    The costs of stroke in Spain by aetiology: The CONOCES study protocol [Los costes del ictus en España según su etiología. El protocolo del estudio CONOCES]
    Source:
    Neurologia 28 (6), 332-339 (2013)
    Abstract:
    Introduction: Patients with stroke associated with non-valvular atrial fibrillation (NVAF) are a specific group, and their disease has a considerable social and economic impact. The primary objective of the CONOCES study, the protocol of which is presented here, is to compare the costs of stroke in NVAF patients to those of patients without NVAF in Spanish stroke units from a societal perspective. Materials and methods: CONOCES is an epidemiological, observational, naturalistic, prospective, multicentre study of the cost of the illness in a sample of patients who have suffered a stroke and were admitted to a Spanish stroke unit. During a 12-month follow-up period, we record sociodemographic and clinical variables, score on the NIH stroke scale, level of disability, degree of functional dependency according to the modified Rankin scale, and use of healthcare resources (hospitalisation at the time of the first episode, readmissions, outpatient rehabilitation, orthotic and/or prosthetic material, medication for secondary prevention, medical check-ups, nursing care and formal social care services). Estimated monthly income, lost work productivity and health-related quality of life measured with the generic EQ-5D questionnaire are also recorded. We also administer a direct interview to the caregiver to determine loss of productivity, informal care, and caregiver burden. Results and conclusions: The CONOCES study will provide more in-depth information about the economic and clinical impact of stroke according to whether or not it is associated with NVAF. © 2012 Sociedad Española de Neurología.
  • Author:
    Inoue Y; Oka Y; Kagimura T; Kuroda K; Hirata K
    Title:
    Reliability, validity, and responsiveness of the Japanese version of International Restless Legs Syndrome Study Group rating scale for restless legs syndrome in a clinical trial setting
    Source:
    Psychiatry Clin Neurosci 67 (6), 412-419 (2013)
    Abstract:
    Aim This study was conducted to verify the reliability, validity, and responsiveness of the Japanese version of the International Restless Legs Syndrome Study Group Rating Scale for restless legs syndrome (J-IRLS) as a sub-study of a clinical trial of pramipexole against restless legs syndrome. Methods After evaluating the test-retest reliability, concurrent validity and construct validity were analyzed. The responsiveness of J-IRLS was confirmed by evaluating the correlations between the changes in J-IRLS total score after treatment, Clinical Global Impression Improvement Scale (CGI-I), and Patient Global Impression. Results Test-retest reliability of J-IRLS was good (intra-class correlation coefficient, 0.877; 95% confidence interval, 0.802-0.925). The correlation coefficient of J-IRLS total score and CGI-S score for the first and second visit was 0.804 and 0.796, respectively (both P < 0.0001). Factor analysis of J-IRLS itemsalone identified a two-factor structure. Exploratory analysis on 10 items of J-IRLS together with the Japanese version of the Pittsburgh Sleep Quality Index revealed that several items on the Japanese version of the Pittsburgh Sleep Quality Index appeared as the third factor. The correlations of CGI-I and Patient Global Impression with change in J-IRLS total score after treatment were highly significant. Conclusions Reliability, validity, and responsiveness of J-IRLS were considered adequate. The scale is highly applicable both for evaluating the severity of restless legs syndrome and for assessing drug efficacy. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.
  • Author:
    Bahnassawy L; Nicklas S; Palm T; Menzl I; Birzele F; Gillardon F; Schwamborn JC
    Title:
    The Parkinson's disease-associated LRRK2 mutation R1441G inhibits neuronal differentiation of neural stem cells
    Source:
    Stem Cells Dev 22 (18), 2487-2496 (2013)
    Abstract:
    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause familial as well as sporadic Parkinson's disease (PD) that is characterized by an age-dependent degeneration of dopaminergic neurons. LRRK2 is strongly expressed in neural stem cells (NSCs), but still the exact molecular function of LRRK2 in these cells remains unknown. By performing a systemic analysis of the gene expression profile of LRRK2-deficient NSCs, we found that the expression of several PD-associated genes, such as oxidation and reduction in mitochondria, are deregulated on LRRK2 absence. Our data, indeed, indicate that LRRK2 regulates the level of cellular oxidative stress and thereby influences the survival of NSCs. Furthermore, the lack of LRRK2 leads to an up-regulation of neuronal differentiation-inducing processes, including the Let-7a pathway. On the other hand, the constitutive mutant of LRRK2(R1441G), known to cause PD, leads to down-regulation of the same pathway. In agreement with the function of Let-7a during neuronal differentiation, LRRK2-deficient NSCs differentiate faster than wild-type cells, while LRRK2(R1441G)-expressing NSCs show impaired neuronal differentiation. These results might help better characterize the molecular mechanisms underlying the role of LRRK2 in NSCs and would further improve potential cell-replacement strategies as well as drug discovery approaches. © Copyright 2013, Mary Ann Liebert, Inc. 2013.
  • Author:
    Ondo WG; Hossain M; Gordon MF; Reess J
    Title:
    Clinical/scientific notes
    Source:
    Neurology 81 (2), 193-194 (2013)
    Abstract:
    no abstract available
  • Author:
    Hamdam J; Sethu S; Smith T; Alfirevic A; Alhaidari M; Atkinson J; Ayala M; Box H; Cross M; Delaunois A; Dermody A; Govindappa K; Guillon J-M; Jenkins R; Kenna G; Lemmer B; Meecham K; Olayanju A; Pestel S; Rothfuss A; Sidaway J; Sison-Young R; Smith E; Stebbings R; Tingle Y; Valentin J-P; Williams A; Williams D; Park K; Goldring C
    Title:
    Safety pharmacology - Current and emerging concepts
    Source:
    Toxicol Appl Pharmacol Article in press (2013)
    Abstract:
    Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. © 2013 Elsevier Inc. All rights reserved.
  • Author:
    Deiana S
    Title:
    Medical use of cannabis. Cannabidiol: A new light for schizophrenia?
    Source:
    Drug Test Anal 5 (1), 46-51 (2013)
    Abstract:
    The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. ln the firsthalf of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabisplant alongside the main constituent Ll9-Tetrahydrocannabinol (THC); these include Cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some SchizopHrenie symptoms, Cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non­ psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can amelierate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia. © 2012 John Wiley &amp; Sons, Ud.
  • Author:
    Bos S
    Title:
    Ciclesonide and tiotropium synergistically inhibit airway eosinophilia in a guinea pig model of chronic asthma
    Source:
    ERS, Barceolna, Spain, Sep 07-09, 2013
  • Author:
    Inoue Y; Oka Y; Kagimura T; Kuroda K; Hirata K
    Title:
    Reliability, validity, and responsiveness of the Japanese version of International Restless Legs Syndrome Study Group rating scale for restless legs syndrome in a clinical trial setting
    Source:
    Psychiatry Clin Neurosci Article in press (2013)
    Abstract:
    Aim: This study was conducted to verify the reliability, validity, and responsiveness of the Japanese version of the International Restless Legs Syndrome Study Group Rating Scale for restless legs syndrome (J-IRLS) as a sub-study of a clinical trial of pramipexole against restless legs syndrome. Methods: After evaluating the test-retest reliability, concurrent validity and construct validity were analyzed. The responsiveness of J-IRLS was confirmed by evaluating the correlations between the changes in J-IRLS total score after treatment, Clinical Global Impression Improvement Scale (CGI-I), and Patient Global Impression. Results: Test-retest reliability of J-IRLS was good (intra-class correlation coefficient, 0.877; 95% confidence interval, 0.802-0.925). The correlation coefficient of J-IRLS total score and CGI-S score for the first and second visit was 0.804 and 0.796, respectively (both P<0.0001). Factor analysis of J-IRLS itemsalone identified a two-factor structure. Exploratory analysis on 10 items of J-IRLS together with the Japanese version of the Pittsburgh Sleep Quality Index revealed that several items on the Japanese version of the Pittsburgh Sleep Quality Index appeared as the third factor. The correlations of CGI-I and Patient Global Impression with change in J-IRLS total score after treatment were highly significant. Conclusions: Reliability, validity, and responsiveness of J-IRLS were considered adequate. The scale is highly applicable both for evaluating the severity of restless legs syndrome and for assessing drug efficacy. © 2013 Japanese Society of Psychiatry and Neurology.
  • Author:
    Caesar M; Zach S; Carlson CB; Brockmann K; Gasser T; Gillardon
    Title:
    Leueine-rich repeat kinase 2 functionally interacts with microtubules and kinase-dependently modulates cell migration
    Source:
    Neurobiol Dis Article in press (2013)
    Abstract:
    Recent studies indicate that the Parkinson's disease-linked leueine-rich repeat kinase 2 (LRRK2) modulates cytoskeletal functions by regulating actin and tubulin dynamics, thereby affecting neurite outgrowth. By interactome analysis we demonstrate that the binding of LRRK2 to tubulins is significantly enhanced by pharmacological LRRK2 inhibition in cells. Co-incubation of LRRK2 with microtubules increased the LRRK2 GTPase activity in a cell-free assay. Destabilization of microtubules causes a rapid decrease in cellular LRRK2(S935) phosphorylation indicating a decreased LRRK2 kinase activity. Moreover, both human LRRK2(G2019S) fibroblasts and mouse LRRK2(R1441G) fibroblasts exhibit alterations in cell migration in culture. Treatment of mouse fibroblasts with the selective LRRK2 inhibitor LRRK2-IN1 reduces cell motility. These findings suggest that LRRK2 and microtubules mutually interact both in non-neuronal cells and in neurons, which might contribute to our understanding of its pathogenic effects in Parkinson's disease. © 2013 Elsevier lnc. All rights reserved.
  • Author:
    Schülert N
    Title:
    Electrophysiological characterization of different animal models for diabetes type-1 and type-Il induced neuropathic pain - what can we learn from spinal recordings?
    Source:
    IMI workshop in Stevenage, UK
  • Author:
    Kroker A
    Title:
    LTP in rat hippocampal slices for characterization of memory enhancing drugs as potential treatment of Alzheimer's disaase
    Source:
    lnvited guest presentation at the Graduale School Biological Sciences, University of Konstanz
  • Author:
    Hobson S
    Title:
    Current perspectives of Alzheimer's Disease Research
    Source:
    Tobe presented at Hochschule Biberach Pharmazeutische Biotechnologie, Jan 22, 2013
  • Author:
    Pryce C R; Azzinnari D; Sigrist H; Seifritz E; Ceci A; Hengerer B
    Title:
    A valid mouse model for the study of the role of inflammatory pathways in depression and novel antidepressant therapy
    Source:
    International Society for Psychoneuroendocrinology annual meeting, Leiden NL, August 20-22, 2013
  • Author:
    Haug KG; Staab A; Dansirikul C; Lehr T
    Title:
    A semi-physiological model of amyloid-b biosynthesis and clearance in human cerebrospinal fluid: A tool for alzheimer's disease research and drug development
    Source:
    J Clin Pharmacol 53 (7), 691-698 (2013)
    Abstract:
    Stable isotope labeling kinetics (SILK) was successfully applied to quantify endogenous amyloid-b (Ab) metabolism in human cerebrospinal fluid (CSF). A semi-physiological model describing Ab biosynthesis and degradation in human CSF and the impact of the g-secretase inhibitor semagacestat should be developed and validated based on digitized data from three published SILK studies. Ab biosynthesis was adequately characterized by six transit compartments. At each transition step, a first-order degradation process was implemented. A two-compartment model best described semagacestat CSF concentration-time profiles. Semagacestat concentrations were linked to the Ab production by an inhibitory Emax model. For model validation, three individual Ab profiles from literature were successfully predicted. Model application demonstrated a 35% decreased Ab elimination rate constant in Alzheimer's disease (AD) patients. Study design optimization revealed that SILK studies could be conducted with significant less sampling points compared to the standard protocol without losing information about the Ab metabolism, if analyzed by the presented model. In conclusion, the analysis outlined the advantages and opportunities of integrating all available data and knowledge into a semi-physiological model. The model can serve as valuable tool for researchers and clinicians interested in the pathology of AD as well as in the development of new therapeutics for AD. © The Author(s) 2013.
  • Author:
    Schapira AHV; McDermott MP; Barone P; Comella CL; Albrecht S; Hsu HH; Massey DH; Mizuno Y; Poewe W; Rascol O; Marek K
    Title:
    Pramipexole in patients with early Parkinson's disease (PROUD): A randomised delayed-start trial
    Source:
    Lancet Neurol 12 (8), 747-755 (2013)
    Abstract:
    Background: In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD). Methods: Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1.5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854. Findings: Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0.4 points, 95% CI -2.2 to 1.4, p=0.65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was -15.1% (SE 2.1) for early and -14.6% (2.0) for delayed pramipexole (difference -0.5 percentage points, 95% CI -5.4 to 4.4, p=0.84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug. Interpretation: By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects. © 2013 Elsevier Ltd.
  • Author:
    Okle O; Stemmer K; Deschl U; Dietrich DR
    Title:
    L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations
    Source:
    Toxicol Sci 131 (1), 217-224 (2013)
    Abstract:
    The cyanobacterial .-N-methylamino-L-alanine (L-BMAA) is described as a low-potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in Guam. The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food. The question thus was raised whether L-BMAA leads to neurodegeneration at nonexcitotoxic conditions. Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins, and subsequent impairment of cellular protein homeostasis were investigated. Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14)C-L-BMAA exposures. Nevertheless, low L-BMAA concentrations (. 0.1mM, 48 h) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the endoplasmic reticulum (ER) stress marker CHOP, and enhanced phosphorylation of elf2. in SH-SY5Y cells. In contrast, high L-BMAA concentrations (. 1mM, 48 h) increased reactive oxygen species and protein oxidization, which were partially ameliorated by coincubation with vitamin E. L-BMAA-mediated cytotoxicity was observable 48 h following . 2mM L-BMAA treatment. Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high-concentration effects such as excitotoxicity and oxidative stress. Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC in Guam.
  • Author:
    Deiana S
    Title:
    Medical use of cannabis. Cannabidiol: A new light for schizophrenia?
    Source:
    Drug Test Anal 5 (1), 46-51 (2013)
    Abstract:
    The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. In the first half of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabis plant alongside the main constituent ..-Tetrahydrocannabinol (THC); these include cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some schizophrenic symptoms, cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non-psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can ameliorate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia.
  • Author:
    Okle O; Stemmer K; Deschl U; Dietrich DR
    Title:
    (L)-BMAA Induced ER Stress and Enhanced Caspase 12 Cleavage in Human Neuroblastoma SH-SY5Y Cells at Low Nonexcitotoxic Concentrations
    Source:
    Toxicol Sci 131 (1), 217-224 (2013)
    Abstract:
    The cyanobacterial .-N-methylamino-L-alanine (L-BMAA) is described as a low-potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in Guam. The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food. The question thus was raised whether L-BMAA leads to neurodegeneration at nonexcitotoxic conditions. Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins, and subsequent impairment of cellular protein homeostasis were investigated. Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14)C-L-BMAA exposures. Nevertheless, low L-BMAA concentrations (. 0.1mM, 48 h) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the endoplasmic reticulum (ER) stress marker CHOP, and enhanced phosphorylation of elf2. in SH-SY5Y cells. In contrast, high L-BMAA concentrations (. 1mM, 48 h) increased reactive oxygen species and protein oxidization, which were partially ameliorated by coincubation with vitamin E. L-BMAA-mediated cytotoxicity was observable 48 h following . 2mM L-BMAA treatment. Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high-concentration effects such as excitotoxicity and oxidative stress. Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC in Guam.
  • Author:
    Paus Marie; Kohl Zacharias; Ben Abdallah; Nada M -B; Galter Dagmar; Gillardon Frank; Winkler Juergen
    Title:
    Enhanced dendritogenesis and axogenesis in hippocampal neuroblasts of LRRK2 knockout mice.
    Source:
    Brain Res 1497, 85-100 (2013)
    Abstract:
    Adult neurogenesis, the formation of new neurons in the mammalian forebrain, is one important mechanism maintaining lifelong neuronal plasticity. The generation and maturation of adult neural stem and progenitor cells is impaired in models of neurodegenerative diseases, in particular Parkinson's disease (PD). Monogenetic forms of PD were identified and associated with several genes including the leucine-rich-repeat kinase 2 (LRRK2). Some of the underlying mechanisms in neurodegenerative diseases are closely linked to neuronal plasticity, and induce changes in adult neurogenesis, neuritic maintenance, synaptic transmission, and neural connectivity. We investigated adult neurogenesis and neuritic development of newly formed neurons in the hippocampal dentate gyrus of LRRK2 knockout mice. Proliferation and survival of newly generated cells were unchanged. However, the expression profile of maturation markers in surviving newly generated cells was altered. While immature neuronal phenotypes were significantly increased, the mature neuronal phenotype of surviving cells remained unchanged. Importantly, the absolute number of immature doublecortin positive neuroblasts was significantly increased in the hippocampus of LRRK2 knockout mice. These neuroblasts presented extended dendritic length with a more complex arborization. Furthermore, LRRK2 deletion resulted in an increased volume of the axonal mossy fiber bundle projecting from dentate granule cells to CA3 pyramidal neurons. Our findings suggest that LRRK2 influences neurogenesis and particularly neuronal morphogenesis. As neurogenesis and the pre-/post- synaptic compartments are significantly altered in PD, our data advance LRRK2 as a potent candidate in addressing neuroregenerative processes. Copyright © 2012 Elsevier B.V. All rights reserved.
  • Author:
    Müller H-P; Kassubek J; Vernikouskaya I; Ludolph AC; Stiller D; Rasche V
    Title:
    Diffusion Tensor Magnetic Resonance Imaging of the Brain in APP Transgenic Mice: A Cohort Study
    Source:
    PloS ONE 8 (6) e67630 (2013)
    Abstract:
    Introduction:Fast in-vivo high resolution diffusion tensor imaging (DTI) of the mouse brain has recently been shown to enable cohort studies by the combination of appropriate pulse sequences and cryogenically cooled resonators (CCR). The objective of this study was to apply this DTI approach at the group level to .-amyloid precursor protein (APP) transgenic mice.Methods:Twelve mice (5 wild type, 7 APP transgenic tg2576) underwent DTI examination at 1562×250 .m3 spatial resolution with a CCR at ultrahigh field (11.7 T). Diffusion images were acquired along 30 gradient directions plus 5 references without diffusion encoding with a total acquisition time of 35 minutes. Fractional anisotropy (FA) maps were statistically compared by whole brain-based spatial statistics (WBSS) at the group level vs. wild type controls.Results:FA-map comparison showed characteristic regional patterns of differences between the groups with localizations associated with Alzheimer's disease in humans, such as the hippocampus, the entorhinal cortex, and the caudoputamen.Conclusion:In this proof-of-principle study, regions associated with amyloid-. deposition could be identified by WBSS of FA maps in APP transgenic mice vs. wild type mice. Thus, DTI in the mouse brain acquired at 11.7 T by use of a CCR was demonstrated to be feasible for cohort studies. © 2013 Müller et al.
  • Author:
    Tse H-F; Wang Y-J; Ahmed Ai-Abdullah M; Pizarro-Borromeo AB; Chiang C-E; Krittayaphong R; Singh B; Vora A; Wang C-X; Zubaid M; Clemens A; Lim P; Hu D
    Title:
    An Asian stroke perspective Stroke prevention in atrial fibrillation
    Source:
    Heart Rhythm 19 (7), 1082-1088 (2013)
    Abstract:
    Despite relatively lower prevalence of atrial fibrillation (AF) in Asians (~1%) than in Caucasians (~2%), Asia has a much higher overall disease burden because of its proportionally larger aged population. For example, on the basis of reported age-adjusted prevalence rates and projected population figures in China, there will be an estimated 5.2 million men and 3.1 million women with AF older than 60 years by year 2050. Stroke is a disabling complication of AF that is of increasing cause for concern in Asians patients. Implementing consensus expert recommendations for managing stroke risk in patients with AF can considerably reduce stroke rates. However, caution is necessary when aligning management of Asian patients with AF to that of their Caucasian counterparts. Current international guidelines and risk stratification tools for AF management are based on findings in predominantly Caucasian populations and may therefore have limited relevance, in certain respects, to Asian patients. Oral anticoagulants play an important role in preventing AF-related stroke. The vitamin K antagonist warfarin is recommended for reducing the risk of stroke and thromboembolism in high-risk patients with nonvalvular AF; however, warfarin interacts with many drugs and food ingredients, which may pose significant challenges in administration and monitoring among Asian patients. Further research is needed to inform specific guidance on the implications of different stroke and bleeding profiles in Asians vs Caucasians. Moreover, there is scope to improve physician perceptions and patient knowledge, as well as considering alternative new oral anticoagulants, for example, direct thrombin inhibitors or factor Xa inhibitors. © 2013 Heart Rhythm Society.
  • Author:
    Worthmann H; Schwartz A; Heidenreich F; Sindern E; Lorenz R; Adams H-A; Flemming A; Luettje K; Walter U; Haertle B; Dengler R
    Title:
    Educational campaign on stroke in an urban population in Northern Germany: Influence on public stroke awareness and knowledge
    Source:
    Int J Stroke 8 (5), 286-292 (2013)
    Abstract:
    Background Public stroke awareness and knowledge may be supportive for stroke prevention and emergency care-seeking behavior after the acute event, which is highly important for early treatment onset. Aims: In an urban population in Northern Germany (Hannover), a six-month stroke educational campaign was conducted. We expected an increase in stroke knowledge and awareness thereafter. Methods: Computer-assisted telephone interviews were randomly conducted among 1004 representative participants before and 1010 immediately after the educational multimedia campaign. The computer-assisted telephone interviews focused on questions about stroke knowledge and interventions remembered. Results: Knowledge of stroke risk factors increased during the campaign for overweight, physical inactivity, old age, and stroke in family (P<0.05). The knowledge of stroke warning signs was low, although it significantly increased during the campaign (P<0.001) as paresis/weakness (46%) and speech problems (31%) were most frequently named. The majority of respondents indicated that the first action after suffering from stroke should be calling emergency care (74% before vs. 84% after campaign, P<0.001). Conclusions: Our data indicate that stroke knowledge and awareness, which could provide earlier presentation to the emergency unit for timely treatment onset, are still low in urban Northern Germany but may decisively be increased by educational campaigns. © 2012 World Stroke Organization.
  • Author:
    Ondo W; Monir H Md; Forrest G M; Reess J
    Title:
    Predictors of placebo response in restless legs syndrome studies
    Abstract:
    Restless legs syndrome (RLS) is a highly prevalent sensorimotor disorder. Effective treatments for RLS have been established in large placebo-controlled trials. These trials have generally employed the International RLS Rating Scale (IRLS) (range 0-40)(1) and Clinical Global Impression of Change (CGI). The interpretation of clinical trials has been mitigated by a large placebo response for both the IRLS and CGI.(2) We wished to evaluate specific patient, scale, and trial design predictors of placebo response.
  • Author:
    Ernsting A; Schwarzer R; Lippke S; Schneider M
    Title:
    'I do not need a flu shot because i lead a healthy lifestyle': Compensatory health beliefs make vaccination less likely
    Source:
    Health Psychol 18 (6), 825-836 (2013)
    Abstract:
    Compensatory health beliefs, a self-defence strategy, were examined in a theory-guided intervention promoting influenza vaccination at the workplace. In total, 851 employees were randomised to one group aimed at enhancing intention formation (standard group) or to another one assisting self-regulation (intervention group). Assessments took place after the intervention and 5 months later, investigating whether the intervention would interfere with compensatory health beliefs. The intervention generated an indirect effect via planning on vaccination. Compensatory health beliefs mediated between intention and behaviour. An interaction between intervention group and compensatory health beliefs on behaviour transpired. At low compensatory health belief levels, the intervention group resulted in more vaccinations than the standard group. © The Author(s) 2012.
  • Author:
    Kroker K S; Moneth J; Kussmaul L; Rast G; Rosenbrock H
    Title:
    Restoring long-term potentiation impaired by amyloid-beta oligomers: Comparison of an acetylcholinesterase inhibitior and selective neuronal nicotinic receptor agonists
    Source:
    Brain Res Bull 96, 28-38 (2013)
    Abstract:
    As nicotinic acetylcholine receptor (nAChR) agonists directly address cholinergic neurotransmission with potential impact on glutamatergic function, they are considered as potential new symptomatic treatment options for Alzheimer's disease compared to the indirectly operating acetylcholinesterase inhibitors such as the current gold standard donepezil. In order to evaluate the therapeutic value of nAChR activation to ameliorate cognitive dysfunction, a direct comparison between ?4?2, ?7 nAChR agonists, and donepezil was performed on the level of an ex vivo experimental model of impaired memory formation. First, we demonstrated that amyloid beta (A?)42 oligomers, which are believed to be the synaptotoxic A?-species causally involved in the pathophysiology of Alzheimer's disease, have a detrimental effect on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices, a widely used cellular model of learning and memory. Second, we investigated the potential of donepezil, the ?4?2 nAChR agonist TC-1827 and the ?7 nAChR partial agonist SSR180711 to reverse A?42 oligomer induced LTP impairment. Donepezil showed only a slight reversal of A?42 oligomer induced impairment of early LTP, and had no effect on A?42 oligomer induced impairment of late LTP. The same was demonstrated for the ?4?2 nAChR agonist TC-1827. In contrast, the ?7 nAChR partial agonist SSR180711 completely rescued early as well as late LTP impaired by A?42 oligomers. As activating ?7 nAChRs was found to be most efficacious in restoring A?42 oligomer induced LTP deficits, targeting ?7 nAChRs might represent a powerful alternative approach for symptomatic treatment of AD. © 2013 Elsevier Inc.
  • Author:
    Hirsch S; Corradini L; Just S; Arndt K; Doods H
    Title:
    The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats
    Source:
    Pain 154 (5), 700-707 (2013)
    Abstract:
    Calcitonin gene-related peptide (CGRP) is known to play a major role in the pathogenesis of pain syndromes, in particular migraine pain. Here we focus on its implication in a rat pain model of inflammation, induced by injection of complete Freund adjuvant (CFA). The nonpeptide CGRP receptor antagonist BIBN4096BS reduces migraine pain and trigeminal neuronal activity. Here we demonstrate that the compound reduces inflammatory pain and spinal neuronal activity. Behavioural experiments reveal a reversal of the CFA-induced mechanical hypersensitivity and monoiodoacetate (MIA)-induced weight-bearing deficit in rats after systemic drug administration. To further investigate the mechanism of action of the CGRP antagonist in inflammatory pain, in vivo electrophysiological studies were performed in CFAinjected rats. Recordings from wide dynamic range neurons in deep dorsal horn layers of the lumbar spinal cord confirmed a reduction of neuronal activity after systemic drug application. The same amount of reduction occurred after topical administration onto the paw, with resulting systemic plasma concentrations in the low nanomolar range. However, spinal administration of BIBN4096BS did not modify the neuronal activity in the CFA model. Peripheral blockade of CGRP receptors by BIBN4096BS significantly alleviates inflammatory pain. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
  • Author:
    Krueger D; Michel K; Allam S; Weiser T; Demir IE; Ceyhan GO; Zeller F; Schemann M
    Title:
    Effect of hyoscine butylbromide (Buscopan®) on cholinergic pathways in the human intestine
    Source:
    Neurogastroenterol Motil Article in press (2013)
    Abstract:
    Background: Hyoscine butylbromide (HBB, Buscopan®) is clinically used to treat intestinal cramps and visceral pain. Various studies, mainly on animal tissues, suggested that its antimuscarinic action is responsible for its spasmolytic effect. However, functional in vitro studies with human tissue have not been performed so far. Methods: We wanted to provide a comprehensive study on the mode of action of HBB in human intestinal samples and investigated HBB (1 nmol L-1-10 ?mol L-1) effects on muscle activity with isometric force transducers and calcium imaging, on epithelial secretion with Ussing chamber technique and on enteric neurons using fast neuroimaging. Key Results: Hyoscine butylbromide concentration dependently reduced muscle contractions, calcium mobilization, and epithelial secretion induced by the muscarinic agonist bethanechol with IC50 values of 429, 121, and 224 nmol L-1, respectively. Forskolin-induced secretion was not altered by HBB. Cholinergic muscarinic muscle and epithelial responses evoked by electrical nerve stimulation were inhibited by 1-10 ?mol L-1 HBB. Moreover, HBB significantly reduced the bethanechol-induced action potential discharge in enteric neurons. Interestingly, we observed that high concentrations of HBB (10 ?mol L-1) moderately decreased nicotinic receptor-mediated secretion, motility, and nerve activity. Conclusions &amp; Inferences: The results demonstrated the strong antimuscarinic action of HBB whereas the nicotinic antagonism at higher concentrations plays at most a moderate modulatory role. The muscle relaxing effect of HBB and its inhibition of muscarinic nerve activation likely explain its clinical use as an antispasmodic drug. Our results further highlight a so far unknown antisecretory action of HBB which warrants further clinical studies on its use in secretory disorders. © 2013 John Wiley &amp; Sons Ltd.
  • Author:
    Fabbrini G; Abbruzzese G; Barone P; Antonini A; Tinazzi M; Castegnaro G; Rizzoli S; Morisky DE; Lessi P; Ceravolo R
    Title:
    Adherence to anti-Parkinson drug therapy in the "REASON" sample of Italian patients with Parkinson's disease: the linguistic validation of the Italian version of the "Morisky Medical Adherence scale-8 items"
    Source:
    Neurol Sci, 1-8 Article in press (2013)
    Abstract:
    Information about patients' adherence to therapy represents a primary issue in Parkinson's disease (PD) management. To perform the linguistic validation of the Italian version of the self-rated 8-Item Morisky Medical Adherence Scale (MMAS-8) and to describe in a sample of Italian patients affected by PD the adherence to anti-Parkinson drug therapy and the association between adherence and some socio-demographic and clinical features. MMAS-8 was translated into Italian language by two independent Italian mother-tongue translators. The consensus version was then back-translated by an English mother-tongue translator. This translation process was followed by a consensus meeting between the authors of translation and investigators and then by two comprehension tests. The translated version of the MMAS-8 scale was then administered at the baseline visit of the "REASON" study (Italian Study on the Therapy Management in Parkinson's disease: Motor, Non-Motor, Adherence and Quality Of Life Factors) in a large sample of PD patients. The final version of the MMAS-8 was easily understood. Mean ± SD MMAS-8 score was 6.1 ± 1.2. There were no differences in adherence to therapy in relationship to disease severity, gender, educational level or decision to change therapy. The Italian version of MMAS-8, the key tool of the REASON study to assess the adherence to therapy, has shown to be understandable to patients with PD. Patients enrolled in the REASON study showed medium therapy adherence. © 2013 Springer-Verlag Italia.
  • Author:
    Schapira AH; McDermott MP; Barone P; Comella CL; Albrecht S; Hsu HH; Massey DH; Mizuno Y; Poewe W; Rascol O; Marek K
    Title:
    Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial
    Source:
    Lancet Neurol Articel in press (2013)
    Abstract:
    Background: In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD). Methods: Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854. Findings: Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal 123I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug. Interpretation: By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects. Funding: Boehringer Ingelheim GmbH. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Hunt K W; Cook A W; Watts R J; Clark C T; Vigers G; Smith D; Metcalf A T; Gunawardana I W; Burkard M; Cox A A; Geck Do M K; Dutcher D; Thomas A A; Rana S; Kallan N C; Delisle R K; Rizzi J P; Regal K; Sammond D; Groneberg R; Siu M; Purkey H; Lyssikatos J P; Marlow A; Liu X; Tang T P
    Title:
    Spirocyclic ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: From hit to lowering of cerebrospinal fluid (CSF) amyloid beta in a higher species
    Source:
    J Med Chem 56 (8), 3379-3403 (2013)
    Abstract:
    A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Abeta), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Abeta is produced by the sequential cleavage of APP by BACE1 and ?-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Abeta in vivo, despite efflux. Starting with spirocycle 1a, we explore structure-activity relationships of core changes, P3 moieties, and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Abeta lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Abeta in rodents and in monkey. © 2013 American Chemical Society.
  • Author:
    O'Donnell M J; Diener H-C; Sacco R L; Panju A A; Vinisko R; Yusuf S
    Title:
    Chronic pain syndromes after ischemic stroke: PRoFESS trial
    Source:
    Stroke 44 (5), 1238-1243 (2013)
    Abstract:
    BACKGROUND AND PURPOSE-: Chronic pain syndromes are reported to be common after stroke, but most previous epidemiological studies have generally included small cohorts of patients with relatively short-term follow-up. In a large cohort with ischemic stroke (Prevention Regimen for Effectively avoiding Second Stroke [PRoFESS] trial), we determined the prevalence, risk factors, and clinical consequence of new poststroke pain syndromes. METHODS-: Within the PRoFESS trial (mean follow-up 2.5 years), a standardized chronic pain questionnaire was administered (at the penultimate follow-up visit) to all participants who reported chronic pain since their stroke and did not have a history of chronic pain before their index stroke. Multivariable logistic regression analyses were used to determine risk factors for poststroke pain (and pain subtypes), and the association between poststroke pain and cognitive (?3 reduction in Mini-Mental State Examination score) and functional decline (?1 increase in m-Rankin). RESULTS-: In total, 15 754 participants were included; of which 1665 participants (10.6%) reported new chronic poststroke pain, and included 431 participants (2.7%) with central poststroke pain, 238 (1.5%) with peripheral neuropathic pain, 208 (1.3%) with pain from spasticity, and 136 participants (0.9%) with pain from shoulder subluxation. More than 1 pain subtype was reported in 86 participants (0.6%). Predictors of poststroke pain included increased stroke severity, female sex, alcohol intake, statin use, depressive symptoms, diabetes mellitus, antithrombotic regimen, and peripheral vascular disease. A new chronic pain syndrome was associated with greater dependence (odds ratio, 2.16; 95% confidence interval, 1.82-2.56). Peripheral neuropathy and pain from spasticity/shoulder subluxation were associated with cognitive decline. CONCLUSIONS-: Chronic pain syndromes are common after ischemic stroke and are associated with increased functional dependence and cognitive decline. © 2013 American Heart Association, Inc.
  • Author:
    Müller H-P; Niessen H G; Kaulisch T; Ludolph A C; Kassubek J; Stiller D
    Title:
    MRI allows for longitudinal quantitative analysis of body fat composition in rats: An analysis of sibutramine-associated changes at the group level
    Source:
    Magn Reson Imaging Article in press (2013)
    Abstract:
    Purpose: Body fat distribution changes are associated with multiple alterations in metabolism. Therefore, the assessment of body fat compartments by MRI in animal models is a promising approach to obesity research. Standard T1-weighted (T1w) whole body MRI was used here to quantify different effects in the subcutaneous and visceral fat compartments in rats under treatment with an anorexiant. Materials and methods: Twenty rats on a high caloric diet were investigated by the identical MRI protocol at baseline and after seven weeks. Ten rats received a treatment with sibutramine, 10 rats served as vehicle control group. To longitudinally assess body fat components, MRI analysis was used with two approaches: 2D slicewise graphic analysis (SGA) was compared with an automated 3D analysis algorithm (3DA). Results: At the group level, fat volume differences showed a longitudinal increase of subcutaneous and visceral fat volumes for the control group, whereas the sibutramine group showed stable subcutaneous fat volumes and decrease in visceral fat volumes. SGA and 3DA volume determination showed significant correlations for subcutaneous fat volume (C = 0.85, p < 0.001), visceral fat volume (C = 0.87, p < 0.001), and total fat volume (C = 0.90, p < 0.001). Conclusion: It could be demonstrated that computer-based analysis of T1w MRI could be used to longitudinally assess changes in body fat compartments in rats at the group level. In detail, it was possible to investigate the effect of sibutramine separate on the fat compartments in rats. © 2013 Elsevier Inc. All rights reserved.
  • Author:
    Ernstin A; Gellert P; Schneider M; Lippke S
    Title:
    A mediator model to predict workplace influenza vaccination behaviour - an application of the health action process approach
    Source:
    Psychol Health 28 (5), 579-592 (2013)
    Abstract:
    Purpose: Applying the health action process approach (HAPA) to vaccination behaviour as a single-event health behaviour to study vaccination adherence and its predictors in a worksite flu vaccination programme. Methods: A total of N = 823 employees participated in a longitudinal survey. Predictors (risk perception, self-efficacy, positive and negative outcome expectancies, intention and planning) were assessed at Time 1, and behaviour was assessed five months later at Time 2. Intention and planning were specified as mediators in a path analytical logistic regression model. Results: Risk perception, self-efficacy and positive as well as negative outcome expectancies predicted intention (R2 =.76). Intention and planning predicted subsequent behaviour, and planning mediated the relation between intention and vaccination behaviour (R2 =.67). In addition, results suggested the adjustment of the theoretical model: risk perception and negative outcome expectancies showed direct effects on behaviour resulting in a significantly better model fit. Conclusions: Findings support the general applicability of the HAPA to vaccination behaviour and the importance of planning for translating intentions into behaviour. However, the adjusted model was superior and underlined the particular role of risk perception and negative outcome expectancies for vaccination behaviour to explain underlying mechanisms in vaccination behaviour. © 2013 Copyright Taylor and Francis Group, LLC.
  • Author:
    Caesar M; Zach S; Carlson C B; Brockmann K; Gasser T; Gillardon F
    Title:
    Leucine-rich repeat kinase 2 functionally interacts with microtubules and kinase-dependently modulates cell migration
    Source:
    Neurobiol Dis 54, 280-288 (2013)
    Abstract:
    Recent studies indicate that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cytoskeletal functions by regulating actin and tubulin dynamics, thereby affecting neurite outgrowth. By interactome analysis we demonstrate that the binding of LRRK2 to tubulins is significantly enhanced by pharmacological LRRK2 inhibition in cells. Co-incubation of LRRK2 with microtubules increased the LRRK2 GTPase activity in a cell-free assay. Destabilization of microtubules causes a rapid decrease in cellular LRRK2(S935) phosphorylation indicating a decreased LRRK2 kinase activity. Moreover, both human LRRK2(G2019S) fibroblasts and mouse LRRK2(R1441G) fibroblasts exhibit alterations in cell migration in culture. Treatment of mouse fibroblasts with the selective LRRK2 inhibitor LRRK2-IN1 reduces cell motility. These findings suggest that LRRK2 and microtubules mutually interact both in non-neuronal cells and in neurons, which might contribute to our understanding of its pathogenic effects in Parkinson's disease. © 2013 Elsevier Inc.
  • Author:
    Hirsch S; Corradini L; Just S; Arndt K; Doods H
    Title:
    The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats
    Source:
    Pain Article in Press (2013)
    Abstract:
    Calcitonin gene-related peptide (CGRP) is known to play a major role in the pathogenesis of pain syndromes, in particular migraine pain. Here we focus on its implication in a rat pain model of inflammation, induced by injection of complete Freund adjuvant (CFA). The nonpeptide CGRP receptor antagonist BIBN4096BS reduces migraine pain and trigeminal neuronal activity. Here we demonstrate that the compound reduces inflammatory pain and spinal neuronal activity. Behavioural experiments reveal a reversal of the CFA-induced mechanical hypersensitivity and monoiodoacetate (MIA)-induced weight-bearing deficit in rats after systemic drug administration. To further investigate the mechanism of action of the CGRP antagonist in inflammatory pain, in vivo electrophysiological studies were performed in CFA-injected rats. Recordings from wide dynamic range neurons in deep dorsal horn layers of the lumbar spinal cord confirmed a reduction of neuronal activity after systemic drug application. The same amount of reduction occurred after topical administration onto the paw, with resulting systemic plasma concentrations in the low nanomolar range. However, spinal administration of BIBN4096BS did not modify the neuronal activity in the CFA model. Peripheral blockade of CGRP receptors by BIBN4096BS significantly alleviates inflammatory pain. © 2013 International Association for the Study of Pain.
  • Author:
    Moreth J; Kroker K S; Schwanzar D; Schnack C; Von Amim C A F; Hengerer B; Rosenbrock H; Kussmaul L
    Title:
    Globular and protofibrillar Abeta aggregates impair neurotransmission by different mechanisms
    Source:
    Biochemistry 52 (8), 1466-1476 (2013)
    Abstract:
    In Alzheimer's disease, substantial evidence indicates the causative role of soluble amyloid beta (Abeta) aggregates. Although a variety of Abeta assemblies have been described, the debate about their individual relevance is still ongoing. One critical issue hampering this debate is the use of di fferent methods for the characterization of endogenous and synthetic peptid e and their intrinsic limitations for distinguishing Abeta aggregates. Here , we used different protocols for the establishment of prefibrillar Abeta assemblies with varying morphologies and sizes and compared them in a head-to-head fashion. Aggregation was characterized via the monomeric peptide over time until spheroidal, protofibrillar, or fibrillar Abeta aggregates were predominant. It could be shown that a change in the ionic environment induced a structural rearrangement, which consequently confounds the delineation of a measured neurotoxicity toward a distinct Abeta assembly. Here, neuronal binding and hippocampal neurotransmission we re found to be suitable to account for the synaptotoxicity to different Abe ta assemblies, based on the stability of the applied Abeta aggregates in these settings. In contrast to monomeric or fibrillar Abeta, different prefibrillar Abeta aggregates targeted neurons and impaired hippocampal neurotransmission with nanomolar potency, albeit by different modalities. S pheroidal Abeta aggregates inhibited NMDAR-dependent long-term potentiation , as opposed to protofibrillar A? aggregates, which inhibited AMPAR-dominat ed basal neurotransmission. In addition, a provoked structural conversion o f spheroidal to protofibrillar Abeta assemblies resulted in a time-dependen t suppression of basal neurotransmission, indicative of a mechanistic switc h in synaptic impairment. Thus, we emphasize the importance of addressing the metastability of prefacto characterized A? aggregates in assigning a biological effect. © 2013 American Chemical Society.
  • Author:
    Paus M; Kohl Z; Ben Abdallah N M-B; Galter D; Gillardon F; Winkler J
    Title:
    ATP-competitive LRRK2 inhibitors interfere with monoclonal antibody binding to the kinase domain of LRRK2 under native conditions. A method to directly monitor the active conformation of LRRK2?
    Source:
    Brain Res 1497, 85-100 (2013)
    Abstract:
    Adult neurogenesis, the formation of new neurons in the mammalian forebrain, is one important mechanism maintaining lifelong neuronal plasticity. The generation and maturation of adult neural stem and progenitor cells is impaired in models of neurodegenerative diseases, in particular Parkinson's disease (PD). Monogenetic forms of PD were identified and associated with several genes including the leucine-rich-repeat kinase 2 (LRRK2). Some of the underlying mechanisms in neurodegenerative diseases are closely linked to neuronal plasticity, and induce changes in adult neurogenesis, neuritic maintenance, synaptic transmission, and neural connectivity. We investigated adult neurogenesis and neuritic development of newly formed neurons in the hippocampal dentate gyrus of LRRK2 knockout mice. Proliferation and survival of newly generated cells were unchanged. However, the expression profile of maturation markers in surviving newly generated cells was altered. While immature neuronal phenotypes were significantly increased, the mature neuronal phenotype of surviving cells remained unchanged. Importantly, the absolute number of immature doublecortin positive neuroblasts was significantly increased in the hippocampus of LRRK2 knockout mice. These neuroblasts presented extended dendritic length with a more complex arborization. Furthermore, LRRK2 deletion resulted in an increased volume of the axonal mossy fiber bundle projecting from dentate granule cells to CA3 pyramidal neurons. Our findings suggest that LRRK2 influences neurogenesis and particularly neuronal morphogenesis. As neurogenesis and the pre-/post- synaptic compartments are significantly altered in PD, our data advance LRRK2 as a potent candidate in addressing neuroregenerative processes. © 2012 Elsevier B.V.
  • Author:
    Gillardon F; Kremmer E; Froehlich T; Ueffing M; Hengerer B; Gloeckner C J
    Title:
    ATP-competitive LRRK2 inhibitors interfere with monoclonal antibody binding to the kinase domain of LRRK2 under native conditions. A method to directly monitor the active conformation of LRRK2?
    Source:
    J Neurosci Methods 214 (1), 62-68 (2013)
    Abstract:
    Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 kinase activity is required for toxicity in neuronal cell cultures suggesting that selective kinase inhibitors may prevent neurodegeneration in patients. Directly monitoring LRRK2 activity in cells would be advantageous for the development of small molecule LRRK2 inhibitors. Here, we demonstrate that a monoclonal anti-LRRK2 antibody directed against the activation segment binds less efficiently to native LRRK2 protein in the presence of ATP-competitive LRRK2 inhibitors. Since kinase inhibitors prevent autophosphorylation and refolding of the activation segment, we hypothesize that the antibody preferentially binds to the active conformation of LRRK2 under native conditions. © 2013 Elsevier B.V.
  • Author:
    Choi BD; Kuan C-T; Cai M; Archer GE; Mitchell DA; Gedeon PC; Sanchez-Perez L; Pastan I; Bigner DD; Sampson JH
    Title:
    Systemic administration of a bispecific antibody EGFRvIII successfully treats intracerebral glioma.
    Source:
    Proc Natl Acad Sci USA 110 (1), 270-275 (2013)
  • Author:
    Schapira AHV; Barone P; Hauser RA; Mizuno Y; Rascol O; Busse M; Debieuvre C; Fraessdorf M; Poewe W
    Title:
    Success rate, efficacy, and safety/tolerability of overnight switching from immediate-to extended-release pramipexole in advanced Parkinson's diesease.
    Source:
    Eur J Neurol 20 (1), 180-187 (2013)
    Abstract:
    Background and purpose: For Parkinson's disease (PD), an extended-release (ER) pramipexole formulation taken once daily, has shown efficacy, safety, and tolerability resembling those of immediate-release (IR) pramipexole taken three times daily. The present study assessed, in advanced PD, the success of an overnight switch from adjunctive IR to ER. Methods: Levodopa users experiencing motor fluctuations were randomized to adjunctive double-blind (DB) placebo, IR, or ER. Amongst completers of >_18 weeks, ER recipients were kept on DB ER, whilst IR recipients were switched overnight to DB ER at unchanged daily dosage. After a DB week, switch success was assessed. During the next.5 weeks, all patients underwent ER titration to optimal open-label maintenance dosage. Results: One week post-switch, 86.2% of 123 IR-to-ER and 83.8% of 105 ER-to-ER patients had 55.15% (or 53-point, for pre-switch scores 55.20) increase on UPDRS Parts II + III, and 77.9% (of 122) and 70.2% (of 104) had 5._1-h increase in daily OFF-time. At 32 weeks, the groups showed comparable improvements from DB baseline (pramipexole inception), including, on UPDRS II + Ill, adjusted mean (SE) changes of -14.8 (1.5) for IR-to-ER and -13.3 (1.6) for ER-to-ER. Rates of premature discontinuation owing to adverse events were 6.5% for IR-to-ER and 4.9% for ER-to-ER. Conclusions: By OFF-time and UPDRS criteria, majorities of patients with advanced PD were successfully switched overnight from pramipexole IR to ER at unchanged daily dosage. During subsequent maintenance, pramipexole showed sustained efficacy, safety, and tolerability, regardless of formulation (IR or ER) in the preceding DB trial. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.
  • Author:
    Antunes-Martins A; Perkins JR; Less J; Hildebrandt T; Orengo C; Bennett DL
    Title:
    Systems biology approaches to finding novel pain mediators.
    Source:
    Wiley Interdiscip Rev Syst Biol Med 5 (1), 11-35 (2013)