Value through Innovation01 September 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.

36 publications regarding Inflammation
  • Author:
    Maedler K; Dharmadhikari G; Schumann DM; Størling J
    Title:
    Interleukin-targeted therapy for metabolic syndrome and type 2 diabetes
    Source:
    Handb Exp Pharmacol 203, 257-278 (2015)
    Abstract:
    Interleukin-beta (IL-beta) is a key regulator of the body.s inflammatory response and is produced after infection, injury, and an antigenic challenge. Cloned in 1984, the single polypeptide IL-beta has been shown to exert numerous biological effects. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, and Type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure, and Type 2 diabetes. The macrophage is the primary source of IL-beta, but epidermal, epithelial, lymphoid, and vascular tissues also synthesize IL-beta Recently, IL-beta production and secretion have also been reported from pancreatic islets. Insulin-producing beta-cells within the pancreatic islets are specifically prone to IL-beta-induced destruction and loss of function. Macrophage-derived IL-beta production in insulin-sensitive organs leads to the progression of inflammation and induction of insulin resistance in obesity. This chapter explains the mechanisms involved in the inflammatory response during diabetes progression with specific attention to the IL-beta signal effects influencing insulin action and insulin secretion. We highlight recent clinical studies, rodent and in vitro experiments with isolated islets using IL-beta as a potential target for the therapy of Type 2 diabetes.
  • 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:
    Schuelert N; Just S; Corradini L; Kuelzer R; Bernloehr C; Doods H
    Title:
    The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons
    Source:
    Eur J Pain 19 (1), 132-142 (2015)
    Abstract:
    Background Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism. Methods Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24 h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration. Results BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons. Conclusion The selective bradykinin B1 receptor antagonist BI113823 reduces CFA-induced mechanical hyperalgesia which is mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors. The selective modulation of CFA-sensitized spinal NS neurons by BI113823 could be a promising property for the treatment of inflammatory pain.
  • Author:
    Hafner S; Wagner K; Wepler M; Matallo J; Gröger M; McCook O; Scheuerle A; Huber-Lang M; Frick M W; eber S; Stahl B; Jung B; Calzia E; Georgieff M; Möller P; Dietl P; Radermacher P; Wagner F
    Title:
    Physiological and Immune-Biological Characterization of a Long-Term Murine Model of Blunt Chest Trauma
    Source:
    Shock Article in Press (2014)
    Abstract:
    ABSTRACT: Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually despite normalized lung mechanics and gas exchange. Anesthetized, spontaneously breathing male C57BL/6J mice underwent a blast wave induced blunt chest trauma or sham procedure. 12 and 24 hours later, blood gases and lung mechanics were measured together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit), heme oxygenase-1 (HO-1), activated Caspase-3, Bcl-xL, and Bax expression (western blotting), nuclear factor-.B activation (electrophoretic mobility shift assay), nitrotyrosine formation, and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by HE and PAS staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase of HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups.Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis.
  • Author:
    Harcken C; Riether D; Liu P; Razavi H; Patel U; Lee T; Bosanac T; Ward Y; Ralph M; Chen Z; Souza D; Nelson RM; Kukulka A; Fadra-Khan TN; Zuvela-Jelaska L; Patel M; Thomson DS; Nabozny GH
    Title:
    Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate
    Source:
    ACS Med Chem Lett 5 (12), 1318-1323 (2014)
    Abstract:
    A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound (R)-39.
  • Author:
    Schuelert N; Just S; Kuelzer R; Corradini L; Gorham LCJ; Doods H
    Title:
    The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model
    Source:
    Eur J Pharmacol 746, 274-281 (2015)
    Abstract:
    Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors. Effect on mechanical hyperalgesia in the Complete Freund's Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24 h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156. In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1 mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100 .M had an effect. In sham controls, J-2156 had no effect on neuronal activity. We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.
  • Author:
    More AS; Kim HM; Khang G; Hildebrandt T; Bernlöhr C; Doods H; Vanhoutte PM; Wu D
    Title:
    Des-Arg9-bradykinin causes kinin B1 receptor mediated endothelium-independent contractions in endotoxin-treated porcine coronary arteries
    Source:
    Pharmacol Res 90, 18-24 (2014)
    Abstract:
    This study examined responses of isolated pig coronary arteries after kinin B1 receptor induction by endotoxin. Des-Arg9-bradykinin (DBK) induced concentration-dependent, endothelium-independent contractions in lipopolysaccharide (LPS)-treated but not untreated arterial rings. The B1-receptor antagonist SSR240612, but not the B2-receptor antagonist HOE140, prevented the endothelium-independent contractions to DBK. The DBK-induced contractions were blocked by indomethacin (nonselective cyclooxygenase [COX] inhibitor), celecoxib (selective COX-2 inhibitor), and terbogrel (thromboxane-prostanoid [TP] receptor antagonist) but not valeryl salicylate (selective COX-1 inhibitor), AH6809 (an E prostanoid [EP] and PGD2 receptor [DP1] receptor antagonist), AL 8810 (a selective PGF2. [FP] receptor antagonist), or RO1138452 (a selective I prostanoid [IP] receptor antagonist). They were attenuated by N-(p-amylcinnamoyl) anthranilic acid (ACA), and by DETCA plus tiron but not by l-NAME. Quantitative RT-PCR revealed excessive up-regulations of mRNA expressions of B1 receptors, COX-2, and thromboxane A synthase 1 (TBXAS1) following LPS incubation, but not of B2 receptors or COX-1. The present data demonstrate that B1 receptors are coupled to COX-2 in causing endothelium-independent contractions in endotoxin-treated pig coronary arteries. Accordingly, kinin B1 receptor induction during inflammation may have a pathological significance in the vasculature, particular in coronary arteries with dysfunctional endothelial cells
  • 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:
    Döhner H; Lübbert M; Fiedler W; Fouillard L; Haaland A; Brandwein JM; Lepretre S; Reman O; Turlure P; Ottmann OG; Müller-Tidow C; Krämer A; Raffoux E; Döhner K; Schlenk RF; Voss F; Taube T; Fritsch H; Maertens J
    Title:
    Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy
    Source:
    Blood 124 (9), 1426-1433 (2014)
    Abstract:
    Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with orwithout volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery)was higher for LDAC+volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival wassignificantly prolonged by LDAC+ volasertib comparedwith LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P5.047). LDAC+ volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856. © 2014 by The American Society of Hematology.
  • Author:
    Schuelert N; Just S; Corradini L; Kuelzer R; Bernloehr C; Doods H
    Title:
    The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons
    Source:
    Eur J Pain Article in Press (2014)
    Abstract:
    Background: Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism. Methods: Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration. Results: BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons. Conclusion: The selective bradykinin B1 receptor antagonist BI113823 reduces CFA-induced mechanical hyperalgesia which is mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors. The selective modulation of CFA-sensitized spinal NS neurons by BI113823 could be a promising property for the treatment of inflammatory pain. © 2014 European Pain Federation - EFIC®.
  • Author:
    Kang H; Kerloc'h A; Rotival M; Xu X; Zhang Q; D'Souza Z; Kim M; Scholz J; Ko J-H; Srivastava; PrashantK; Genzen JonathanR; Cui W; Aitman TimothyJ; Game L; Melvin JamesE; Hanidu A; Dimock J; Zheng J; Souza D Behera; Aruna K; Nabozny G; Cook H; Bassett JH; Williams GrahamR; Li J; Vignery A; Petretto E; Behmoaras J
    Title:
    Kcnn4 Is a Regulator of Macrophage Multinucleation in Bone Homeostasis and Inflammatory Disease
    Source:
    Cell Rep Article in Press (2014)
    Abstract:
    Macrophages can fuse to form osteoclasts in bone or multinucleate giant cells (MGCs) as part of the immune response. We use a systems genetics approach in rat macrophages to unravel their genetic determinants of multinucleation and investigate their role in both bone homeostasis and inflammatory disease. We identify a trans-regulated gene network associated with macrophage multinucleation and Kcnn4 as being the most significantly trans-regulated gene in the network and induced at the onset of fusion. Kcnn4 is required for osteoclast and MGC formation in rodents and humans. Genetic deletion of Kcnn4 reduces macrophage multinucleation through modulation of Ca2+ signaling, increases bone mass, and improves clinical outcome in arthritis. Pharmacological blockade of Kcnn4 reduces experimental glomerulonephritis. Our data implicate Kcnn4 in macrophage multinucleation, identifying it as a potential therapeutic target for inhibition of bone resorption and chronic inflammation. © 2014 The Authors.
  • Author:
    Wunder A; Thiele A; Koslowski F; Gantner F; Niessen H G
    Title:
    Nuclear imaging to support anti-inflammatory drug discovery and development
    Source:
    Q J Nucl Med Mol Imaging 58 (3), 290-298 (2014)
    Abstract:
    Nuclear medicine contributes important tools to support antiinflammatory drug discovery and development in many ways. The support provided is manifold: new molecular entities (NME, either small molecules or biologics) labeled with radioisotopes can be applied in animal models and humans to measure biodistribution, target engagement, and pharmacokinetics. In addition, nuclear imaging techniques can be used to select or enrich the patient populations in clinical trials, to assess disease activity, target status and distribution and to quantify response to therapeutic interventions. In the first part of this review we will outline how nuclear imaging techniques can be applied to support informed decision making in drug development. In the second part, we will briefly highlight the use of nuclear imaging of inflammation in drug development in selected diseases, specifically rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), atherosclerosis (ATS) and as an emerging topic cancer.
  • Author:
    Azzinnari D; Sigrist H; Staehli S; Palme R; Hildebrandt T; Leparc G; Hengerer B; Seifritz E; Pryce CR
    Title:
    Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function
    Source:
    Neuropharmacology 85, 328-341 (2014)
    Abstract:
    In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Kaulisch T; Corradini L; Stiller D
    Title:
    Assessment of inflammatory Component in the Mono- Iodoacetate (MIA) Model of Osteoarthritis by MRI
    Source:
    Annual Meeting of the ISMRM, Milano, Italy, May 10-16,2014
  • Author:
    Hall TS; Herrscher TE; Jarolim P; Fagerland MW; Jensen T; Agewall S; Atar D; Hallén J
    Title:
    Myeloid-related protein-8/14 and C-reactive protein in individuals evaluated for obstructive sleep apnea
    Source:
    Sleep Med 15 (7), 762-768 (2014)
    Abstract:
    Background: Obstructive sleep apnea (OSA) and obesity are often present concomitantly. Their potential contribution to inflammation remains an ongoing debate. The objectives of this study were to investigate whether variables of sleep-disordered breathing are associated with levels of myeloid-related protein-8/14 (MRP-8/14) or C-reactive protein (CRP), and to characterize how adiposity interacts with these associations in individuals evaluated for possible OSA. Methods: Consecutive individuals referred to Lovisenberg Diakonale Hospital's sleep laboratory between 1st October 2009 and 1st March 2010 were included. We characterized the biomarker distribution sampled the morning after sleep and related these to clinical characteristics and variables recorded during polygraphy or polysomnography. Results: Of the total study population of 222 individuals, 161 (72.5%) were diagnosed with OSA (apnea-hypopnea index (AHI) .5/h). In baseline models (multiple median regression adjusted for age and sex), AHI was independently associated with MRP-8/14 (P= 0.025) and CRP (P<. 0.001). The associations were attenuated after the addition of body mass index (BMI), but remained statistically significant for CRP (P= 0.025). However, in final models adjusted for additional factors (systolic blood pressure, cholesterol:high-density lipoprotein ratio, glycosylated haemoglobin, smoking, and cardiovascular disease), only average oxygen saturation for MRP-8/14 (P= 0.028) and oxygen desaturation index (ODI) for CRP (P= 0.037) remained independent predictors of inflammation, whereas AHI lost its predictive value (MRP-8/14; P= 0.30 and CRP; P= 0.092). The association between several variables of sleep-disordered breathing and inflammation were stronger in individuals with a higher BMI (P for interaction <0.05 for AHI, nadir oxygen saturation, and time <90% oxygen saturation). Conclusions: No definitive indication of independent immunological activity resulting from apneas and hypopneas was found in final models adjusted for other factors associated with inflammation, whereas average oxygen saturation for MRP-8/14 and ODI for CRP remained statistically significant predictors. Interactions were observed between BMI and several variables of sleep-disordered breathing on MRP-8/14 and CRP levels. © 2014 Elsevier B.V.
  • 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:
    Dawes JM; Antunes-Martins A; Perkins JR; Paterson KJ; Sisignano M; Schmid R; Rust W; Hildebrandt T; Geisslinger G; Orengo C; Bennett DL; McMahon SB
    Title:
    Genome-wide transcriptional profiling of skin and dorsal root ganglia after ultraviolet-B-induced inflammation
    Source:
    PLoS ONE 9 (4) art.No.A1462 (2014)
    Abstract:
    Ultraviolet-B (UVB)-induced inflammation produces a dose-dependent mechanical and thermal hyperalgesia in both humans and rats, most likely via inflammatory mediators acting at the site of injury. Previous work has shown that the gene expression of cytokines and chemokines is positively correlated between species and that these factors can contribute to UVB-induced pain. In order to investigate other potential pain mediators in this model we used RNA-seq to perform genome-wide transcriptional profiling in both human and rat skin at the peak of hyperalgesia. In addition we have also measured transcriptional changes in the L4 and L5 DRG of the rat model. Our data show that UVB irradiation produces a large number of transcriptional changes in the skin: 2186 and 3888 genes are significantly dysregulated in human and rat skin, respectively. The most highly up-regulated genes in human skin feature those encoding cytokines (IL6 and IL24), chemokines (CCL3, CCL20, CXCL1, CXCL2, CXCL3 and CXCL5), the prostanoid synthesising enzyme COX-2 and members of the keratin gene family. Overall there was a strong positive and significant correlation in gene expression between the human and rat (R = 0.8022). In contrast to the skin, only 39 genes were significantly dysregulated in the rat L4 and L5 DRGs, the majority of which had small fold change values. Amongst the most up-regulated genes in DRG were REG3B, CCL2 and VGF. Overall, our data shows that numerous genes were up-regulated in UVB irradiated skin at the peak of hyperalgesia in both human and rats. Many of the top up-regulated genes were cytokines and chemokines, highlighting again their potential as pain mediators. However many other genes were also up-regulated and might play a role in UVB-induced hyperalgesia. In addition, the strong gene expression correlation between species re-emphasises the value of the UVB model as translational tool to study inflammatory pain. © 2014 Dawes et al.
  • Author:
    Wollin L; Maillet I; Quesniaux V; Holweg A; Ryffel B
    Title:
    Antifibrotic and anti-inflammatory activity of the Tyrosine Kinase inhibitor Nintedanib in Experimental Models Of Lung Fibrosiss
    Source:
    J Pharmacol Exp Ther 349 (2), 209-220 (2014)
    Abstract:
    The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis. To explore its mode of action, nintedanib was tested in human lung fibroblasts and mouse models of lung fibrosis. Human lung fibroblasts expressing platelet-derived growth factor (PDGF) receptor-A and -b were stimulated with platelet-derived growth factor BB (homodimer) (PDGF-BB). Receptor activation was assessed by autophosphorylation and cell proliferation by bromodeoxyuridine incorporation. Transforming growth factor b (TGFb)-induced fibroblast to myofibroblast transformation was determined by a-smooth muscle actin (aSMA) mRNA analysis. Lung fibrosis was induced in mice by intratracheal bleomycin or silica particle administration. Nintedanib was administered every day by gavage at 30, 60, or 100 mg/kg. Preventive nintedanib treatment regimen started on the day that bleomycin was administered. Therapeutic treatment regimen started at various times after the induction of lung fibrosis. Bleomycin caused increased macrophages and lymphocytes in the bronchoalveolar lavage (BAL) and elevated interleukin-1b (IL-1b), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in lung tissue. Histology revealed chronic inflammation and fibrosis. Silica-induced lung pathology additionally showed elevated BAL neutrophils, keratinocyte chemoattractant (KC) levels, and granuloma formation. Nintedanib inhibited PDGF receptor activation, fibroblast proliferation, and fibroblast to myofibroblast transformation. Nintedanib significantly reduced BAL lymphocytes and neutrophils but not macrophages. Furthermore, interleukin-1b, KC, TIMP-1, and lung collagen were significantly reduced. Histologic analysis showed significantly diminished lung inflammation, granuloma formation, and fibrosis. The therapeutic effect was dependent on treatment start and duration. Nintedanib inhibited receptor tyrosine kinase activation and the proliferation and transformation of human lung fibroblasts and showed antifibrotic and anti-inflammatory activity in two animal models of pulmonary fibrosis. These results suggest that nintedanib may impact the progressive course of fibrotic lung diseases such as idiopathic pulmonary fibrosis.Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
  • Author:
    Kaulisch T; Corradini L; Stiller D
    Title:
    Assessment of inflammatory Component in the Monolodoacetate (MIA) Model of Osteoarthritis by MRI
    Source:
    Annual Meeting og the ISMRM, Milano, Italy, May 10-16, 2014
  • Author:
    Sparkenbaugh EM; Chantrathammachart P; Mickelson J; Van Ryn J; Hebbel RP; Monroe DM; Mackman N; Key NS; Pawlinski R
    Title:
    Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease
    Source:
    Blood 123 (11), 1747-1756 (2014)
    Abstract:
    Activation of coagulation and vascular inflammation are prominent features of sickle cell disease (SCD). Previously, we have shown that inhibition of tissue factor (TF) attenuates activation of coagulation and vascular inflammation in mouse models of SCD. In this study, we examined the mechanism by which coagulation proteases enhance vascular inflammation in sickle BERK mice. To specifically investigate the contribution of FXa and thrombin, mice were fed chow containing either rivaroxaban or dabigatran, respectively. In addition, we used bone marrow transplantation to generate sickle mice deficient in either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) on nonhematopoietic cells. FXa inhibition and PAR-2 deficiency in nonhematopoietic cells attenuated systemic inflammation, measured by plasma levels of interleukin-6 (IL-6). In contrast, neither thrombin inhibition nor PAR-1 deficiency in nonhematopoietic cells affected plasma levels of IL-6 in sickle mice. However, thrombin did contribute to neutrophil infiltration in the lung, independently of PAR-1 expressed by nonhematopoietic cells. Furthermore, the TF-dependent increase in plasma levels of soluble vascular cell adhesion molecule-1 in sickle mice was not mediated by FXa or thrombin. Our data indicate that TF, FXa, and thrombin differentially contribute to vascular inflammation in a mouse model of SCD. © 2014 by The American Society of Hematology.
  • 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 Article in Press (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-1beta 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 alpha-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:
    Tauber J; Opatz T
    Title:
    Synthesis of Anti-inflammatory Macrolactones: (S)-Curvularin and Derivatives
    Source:
    Poster for FLOHET-15 in Gainesville/Florida and for Frühjahrssymposium des Jungchemikerforums der GDCh in Jena
  • Author:
    Profita M; Albano GD; Riccobono L; Di Sano C; Montalbano AM; Gagliardo R; Anzalone G; Bonanno A; Pieper MP; Gjomarkaj M
    Title:
    Increased levels of Th17 cells are associated with non-neuronal acetylcholine in COPD patients
    Source:
    Immunobiology Article in press (2014)
    Abstract:
    T-lymphocytes, including Th17-cells and T-cells expressing acetylcholine (ACh), are key components of systemic inflammation in chronic obstructive pulmonary disease (COPD). We investigated whether ACh promotes Th17 cells in COPD. ACh, IL-17A, IL-22, ROR.t, FOXP3 expression and AChIL-17A, AChIL-22, AChROR.t coexpression was evaluated in peripheral blood mononuclear cells (PBMC) from COPD patients (n = 16), healthy smokers (HS) (n = 12) and healthy control subjects (HC) (n = 13) (cultured for 48 h with PMA) by flow cytometry. Furthermore, we studied the effect of Tiotropium (Spiriva®) (100 nM) and Olodaterol (1 nM) alone or in combination, and of hemicholinium-3 (50 .M) on AChIL-17A, AChIL-22, AChROR.t, and FOXP3 expression in CD3+PBT-cells of PBMC from COPD patients (n = 6) cultured for 48 h with PMA. CD3+PBT-cells expressing ACh, IL-17A, IL-22 and ROR.t together with CD3+PBT-cells co-expressing AChIL-17A, AChIL-22 and AChROR.t were significantly increased in COPD patients compared to HC and HS subjects with higher levels in HS than in HC without a significant difference. CD3+FOXP3+PBT-cells were increased in HS than in HC and COPD. Tiotropium and Olodaterol reduced the percentage of CD3+PBT-cells co-expressing AChIL-17A, AChIL-22, and AChROR.t while increased the CD3+FOXP3+PBT-cells in PBMC from COPD patients, cultured in vitro for 48 h, with an additive effect when used in combination. Hemicholnium-3 reduced the percentage of ACh+IL-17A+, ACh+IL-22+, and ACh+ROR.t+ while it did not affect FOXP3+ expression in CD3+PBT-cells from cultured PBMC from COPD patients. We concluded that ACh might promote the increased levels of Th17-cells in systemic inflammation of COPD. Long-acting .2-agonists and anticholinergic drugs might contribute to control this event. © 2014.
  • Author:
    Vallon V; Gerasimova M; Rose MA; Masuda T; Satriano J; Mayoux E; Koepsell H; Thomson SC; Rieg T
    Title:
    SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice
    Source:
    Am J Physiol 306 (2), F194-F204 (2014)
    Abstract:
    Our previous work has shown that gene knockout of the sodium-glucose cotransporter SGLT2 modestly lowered blood glucose in streptozotocin-diabetic mice (BG; from 470 to 300 mg/dl) and prevented glomerular hyperfiltration but did not attenuate albuminuria or renal growth and inflammation. Here we determined effects of the SGLT2 inhibitor empagliflozin (300 mg/kg of diet for 15 wk; corresponding to 60-80 mg.kg-1.day-1) in type 1 diabetic Akita mice that, opposite to streptozotocin-diabetes, upregulate renal SGLT2 expression. Akita diabetes, empagliflozin, and Akita + empagliflozin similarly increased renal membrane SGLT2 expression (by 38-56%) and reduced the expression of SGLT1 (by 33-37%) vs. vehicle-treated wild-type controls (WT). The diabetes-induced changes in SGLT2/ SGLT1 protein expression are expected to enhance the BG-lowering potential of SGLT2 inhibition, and empagliflozin strongly lowered BG in Akita (means of 187-237 vs. 517-535 mg/dl in vehicle group; 100-140 mg/dl in WT). Empagliflozin modestly reduced GFR in WT (250 vs. 306 (xl/min) and completely prevented the diabetes-induced increase in glomerular filtration rate (GFR) (255 vs. 397 (xl/min). Empagliflozin attenuated increases in kidney weight and urinary albumin/creatinine ratio in Akita in proportion to hyperglycemia. Empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose balanced the inhibition of glucose reabsorption. Empagliflozin attenuated/prevented the increase in systolic blood pressure, glomerular size, and molecular markers of kidney growth, inflammation, and gluconeogenesis in Akita. We propose that SGLT2 inhibition can lower GFR independent of reducing BG (consistent with the tubular hypothesis of diabetic glomerular hyperfiltration), while attenuation of albuminuria, kidney growth, and inflammation in the early diabetic kidney may mostly be secondary to lower BG.
  • Author:
    Konstan MW; Döring G; Heltshe SL; Lands LC; Hilliard KA; Koker P; Bhattacharya S; Staab A; Hamilton A
    Title:
    A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis
    Source:
    J Cystic Fibros Article in press (2014)
    Abstract:
    Background: Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB4-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 BS in CF patients. Methods: CF patients aged . 6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV1 and incidence of pulmonary exacerbation. Results: After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38). Conclusions: While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events. © 2014 European Cystic Fibrosis Society.
  • Author:
    Kuzmich D; Bentzien J; Betageri R; DiSalvo D; Fadra-Khan T; Harcken C; Kukulka A; Nabozny G; Nelson R; Pack E; Souza D; Thomson D
    Title:
    Function-regulating pharmacophores in a sulfonamide class of glucocorticoid receptor agonists
    Source:
    Bioorg Med Chem Lett Article in press (2013)
    Abstract:
    A class of alpha-methyltryptamine sulfonamide glucocorticoid receptor (GR) modulators was optimized for agonist activity. The design of ligands was aided by molecular modeling, and key function-regulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell based assays. Compound 27 was profiled in vitro and in vivo in models of inflammation. Analogs could be rapidly prepared in a parallel approach from aziridine building blocks. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    R. Lewis; L. Chachi; Y. Amrani; P. Bradding
    Title:
    A comparison of b2-adrenoceptor desensitisation induced by olodaterol and formoterol in human lung mast cells and airway smooth muscle cells
    Source:
    ERS, Barcelona, Spain, Sep 7-9, 2013
  • Author:
    Schülert N; Corradini L; Just S; Bernlöhr C; Külzer R; Doods H
    Title:
    The Bradykinin B1 receptor antagonist BI 113823 reverses hyperalgesia by reducing mechanosensitivity of peripheral afferents and nociceptive-specific dorsal horn neruons in a rat model of inflammatory pain
    Source:
    Deutscher Schmerzkongress
  • Author:
    Lacy BE; Wang F; Bhowal S; Schaefer E
    Title:
    On-demand hyoscine butylbromide for the treatment of self-reported functional cramping abdominal pain
    Source:
    Scand J Gastroenterol 48 (8), 926-935 (2013)
    Abstract:
    Objective. Hyoscine butylbromide (HBB) has been used for 60 years to treat cramping abdominal pain, but scientific evidence to support on-demand use is limited. The aim of this study was to identify a meaningful efficacy end point that differentiates between the effects of HBB (20-100 mg/day) and placebo when used on demand. Materials & methods. 175 patients were treated in a randomized, double-blind, placebo-controlled, two-arm parallel group study. After a 4-week run-in period, patients used HBB to treat 2 distinct episodes of abdominal pain associated with cramping (APC). Patients entered data into an electronic diary for up to 4 h/episode. Pain intensity was assessed using an 11-point numerical pain rating scale (NPRS). Patients were allowed to self-medicate with up to 4 additional doses of HBB every 30 min. Results. The adjusted mean difference for the change from baseline during the 4-h observation period for a reduction in abdominal pain was -0.7 (95% confidence interval (CI) -1.3, -0.1, p = 0.016) for episode 1 and -0.6 (95% CI -1.2, 0.0, p = 0.051) for episode 2. Patients in the HBB group recorded a clinically relevant reduction of at least 2 points on the NPRS (approximately 30% pain relief) earlier than patients in the placebo group (HBB: 45 min, placebo: 60 min). Reported adverse events were infrequent in both groups (10.2% and 10.3%). Conclusions. HBB is effective in the treatment of recurrent APC and is safe and well tolerated when used on demand. The change from baseline in the intensity of APC using the 11-point NPRS distinguished HBB from placebo. © 2013 Informa Healthcare.
  • Author:
    McHugh Kevin P; Crotti Tania N; Li Jun; Hill Jon; Nabozny Gerald H; Goldring Steven R
    Title:
    Novel targets for blocking osteoclast-mediated resorption in inflammatory disorders.
    Abstract:
    -
  • Author:
    Schleputz M; Bernau M; Kanzler SS; Uhlig S; Martin C
    Title:
    Neurally-induced bronchoconstriction in precision-cut lung slices of guinea pigs is modulated by lipopolysaccharide and neurotrophins.
    Source:
    Naunyn Schmiedebergs Arch Pharmakol 386 (1), 71 (2013)
    Abstract:
    Rationale: Inflammation, a hallmark of asthma and COPD, contributes to neural modulation and consequential airway hyperresponsiveness (AHR). To further study this concept the present investigation aimed to characterize the effect of lipopolysaccharide (LPS) as well as neurotrophins and their receptors on neurally-induced bronchoconstriction (BC) in precision-cut lung slices (PCLS) of guinea pigs. Methods: PCLS were prepared from Dunkin Hartley guinea pigs. PCLS were incubated with LPS (500 ng/mL) for 18 h to mimic inflammation and thereafter TNF release was measured by ELISA. Neurotrophic receptors (TrkA, -B, -C, p75NTR, GFR.alpha.) were analyzed by Western-blotting. Electric field stimulation (EFS) of PCLS was performed to induce neural BC. BC was monitored by videomicroscopy and the initial airway area was defined as 100% initial airway area (IAA). Frequency-response curves (1-100 Hz) were conducted on untreated PCLS (control) or on pretreated PCLS, incubated with LPS (500 ng/mL for 18 h), nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), or glial derived neurotrophic factor (GDNF) (each at 50 ng/mL for 20 min or 24 h). Results: LPS application in guinea pig PCLS led to a 128-fold induction of TNF release and augmented BC in frequency-response curves (44%-IAA vs. 63%-IAA in control for frequencies .gtoreq. 50 Hz). The expression of TrkA, -B, -C, p75NTR and GFR.alpha. was detected in PCLS. Among the neurotrophins studied NGF and GDNF (44%-IAA and 41%-IAA, respectively, vs. 63%-IAA in control for frequencies .gtoreq. 50 Hz) increased the neurallyinduced BC after short incubation periods. In contrast, after incubation for 24 h only NT3 (46%-IAA for frequencies .gtoreq. 50 Hz) enhanced BC in comparison to the control (61%-IAA for frequencies .gtoreq. 50 Hz). Conclusion: Since TNF levels were elevated after LPS, a pro-inflammatory state could be confirmed in PCLS, leading to AHR after EFS. Distinct neurotrophic factors are capable to induce AHR. The fast effects of NGF and GDNF may be based on direct modulation of neurotransmission, i.e. action potential profiles, whereas NT3 may involve altered transcription based changes of nerve function.
  • Author:
    Miriyala S; Panchatcharam M; Landar A; Ramanujam M; Chatterjee S; Muthuswamy A
    Title:
    The janus of oxidative stress signaling in different pathophysiological conditions
    Source:
    Oxidative Med Cell Longevity art no 708796 (2013)
    Abstract:
    no abstract available
  • 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:
    Wang J; Shiratori I; Uehori J; Ikawa M; Arase H
    Title:
    Neutrophil infitration during inflammation is regulated by PLRalpha via modulation of integrin activation.
  • Author:
    Blech M; Peter D; Fischer P; Bauer MMT; Hafner M; Zeeb M; Nar H
    Title:
    One target - two different binding modes: Structural insights into gevokizumab and canakinumab interactions to interleukin-1beta.
    Source:
    J Mol Biol 425 (1), 94-111 (2013)
    Abstract:
    Interleukin-1beta (IL-1beta) is a key orchestrator in inflammatory and several immune responses. IL-1beta exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1 RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1beta monoclonal antibodies. Canakinumab is known to neutralize IL-1beta by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1beta bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1beta signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1beta. Furthermore, we characterized the epitopes on IL-1beta employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1beta and provide insight into the mechanisms leading to their distinct modulation of IL-1beta signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1beta causes competitive inhibition of the association of IL-1beta and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1beta and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1beta pathway attenuation.
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.