NEUROFIT



PUBLICATIONSMethyllycaconitine- and scopolamine-induced cognitive dysfunction: differential reversal effect by cognition-enhancing drugsEmile Andriambeloson ·?Bertrand Huyard?·?Etienne Poiraud?·Stéphanie WagnerPharmacol Res Perspect.?2014 Aug;2(4):e00048. doi: 10.1002/prp2.48. Epub 2014 Jun 9.There is a growing body of evidence pointing to the pivotal role of alpha-7 nicotinic acetylcholine receptor (α7 nAchR) dysfunction in?cognitivedisorders such as Alzheimer's disease or schizophrenia. This study was undertaken to establish and characterize an in vivo model for?cognitivedisorder secondary to the blockade of α7 nAChR by its specific antagonist,?methyllycaconitine?(MLA). The results show that MLA elicited?cognitivedysfunction as assessed by reduced spontaneous alternation of mice in the T-maze. The maximal effect of MLA produced 25-30% reduction in the spontaneous alternation of mice, a level comparable with that?induced?by the muscarinic antagonism of?scopolamine. Donepezil and galantamine fully reversed both MLA and?scopolamine-induced?cognitive?dysfunction. However, the ED50 of donepezil and galantamine was significantly shifted to the left in the MLA- compared to?scopolamine-treated mice (0.0005 and 0.002 mg/kg for donepezil; 0.0003 and 0.7 mg/kg for galantamine). Moreover, memantine elicited marked reversion of?cognitive?dysfunction (up to 70%) in MLA-treated mice while only a weak reversal effect at high dose of memantine (less than 20%) was observed in?scopolamine-treated mice. The above findings indicate that MLA-induced?cognitive?dysfunction in the mouse is highly sensitive and more responsive to the current procognitive drugs than the traditional?scopolamine-based assay. Thus, it can be of value for the preclinical screening and profiling of cognition-enhancing drugs.Treatment with Actovegin (R) Improves Sensory Nerve Function and Pathology in Streptozotocin-Diabetic Rats via Mechanisms Involving Inhibition of PARP ActivationA Dieckmann?·?M Kriebel?· E Andriambeloson ·?D Ziegler?·?M. W. ElmlingerExp Clin Endocrinol Diabetes.?2012 Mar;120(3):132-8. doi: 10.1055/s-0031-1291248. Epub 2011 Oct 21.BACKGROUND: Diabetic neuropathy is one of the most severe complications of diabetes, affecting approximately one-third of diabetic patients. We investigated the potential neuroprotective effect of?Actovegin?, a deproteinized hemoderivative of calf blood, in an animal model of diabetic neuropathy.METHODS :A single intravenous injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in male Sprague-Dawley rats.?Actovegin? (200 or 600 mg/kg) was administered intraperitoneally from day 11 to day 40 post-STZ exposure. N-acetylcysteine (NAC) was used as a positive control and was added to drinking water (0.2 g/l) from day 2 until day 40. Measurements to assess efficacy included sensory nerve conduction velocity (SNCV), intraepidermal nerve fiber density (IENFD), and poly(ADP-ribose) content.RESULTS: A decrease (35%) in sensory nerve conduction velocity (SNCV) was seen in STZ-induced diabetic rats from day 10 post-STZ administration and persisted at days 25 and 39. At study completion (day 41), a decrease (32%) in intraepidermal nerve fiber density (IENFD) was found in hind-paw skin biopsies from STZ-rats. Reduced SNCV and IENFD were significantly ameliorated by both doses of?Actovegin?. More-over, 600 mg/kg?Actovegin? markedly decreased poly(ADP-ribose) polymerase (PARP) activity in sciatic nerves from STZ-diabetic rats as assessed by poly(ADP-ribose) content.CONCLUSION: Actovegin? improved several para-meters of experimental diabetic neuropathy via mechanisms involving suppression of PARP activation, providing a rationale for?treatment?of this disease in humansSLV330, a cannabinoid CB1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodentsN M W J de Bruin?·?J Prickaerts?·?J H M Lange?·?S Akkerman?· E Andriambeloson ·?M de Haan?·?J Wijnen?·?M van Drimmelen?·?E Hissink?·?L Heijink?·?C G KruseNeurobiol Learn Mem.?2010 May;93(4):522-31. doi: 10.1016/j.nlm.2010.01.010. Epub 2010 Feb 2.Cannabinoid CB(1) receptor (CB(1)R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB(1)R antagonist?SLV330?(doses ranging from 0.3 to 10mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of?SLV330?were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept, approved for symptomatic treatment of Alzheimer's disease) and nicotine were used as reference compounds.?SLV330?markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3mg/kg. In the ORT, we have found that combined administration of subthreshold doses of?SLV330?(1mg/kg, p.o.) and the AChEI donepezil (0.1mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of?SLV330?and donepezil on cognitive impairment. Finally,?SLV330?was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3mg/kg (p.o.). In conclusion, the CB(1)R antagonist?SLV330?was found to clearly improve memory in several preclinical models for cognitive impairment.Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophyMagali Michaud?·?Thomas Arnoux?·?Serena Bielli?·?Estelle Durand?·Yann Rotrou?·?Sibylle Jablonka?·?Fabrice Robert?·?Marc Giraudon-Paoli?·?Markus Riessland?·?Marie-Geneviève Mattei?· Emile Andriambeloson ·?Brunhilde Wirth?·?Michael Sendtner?·?Jorge Gallego?·?Rebecca M Pruss?·?Thierry BordetNeurobiol Dis.?2010 Apr;38(1):125-35. doi: 10.1016/j.nbd.2010.01.006. Epub 2010 Jan 18.Spinal?muscular?atrophy?(SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein leading to muscle paralysis and respiratory failure. In?mouse, introducing the human SMN2 gene partially rescues Smn(-)(/)(-) embryonic lethality. However current models were either too severe or nearly unaffected precluding convenient drug testing for SMA. We report here?new?SMN2;Smn(-/-) lines carrying one to four copies of the human SMN2 gene. Mice carrying three SMN2 copies exhibited an intermediate phenotype with delayed appearance of motor?defects?and developmental?breathing?disorders?reminiscent of those found in severe SMA patients. Although normal at birth, at 7 days of age respiratory rate was decreased and apnea frequency was increased in SMA mice in parallel with the appearance of?neuromuscular?junction?defects?in the diaphragm. With median survival of 15 days and postnatal onset of neurodegeneration, these mice could be an important tool for evaluating?new?therapeutics.Animal Models of Collagen-Induced ArthritisStéphanie Wagner?·?Julien Bindler?· Emile AndriambelosonCurr Protoc Pharmacol.?2008 Dec;Chapter 5:Unit 5.51. doi: 10.1002/0471141755.ph0551s43.Collagen-induced arthritis in rats is associated with inflammatory polyarthritis, sharing clinical and pathological features with those of human rheumatoid arthritis (RA). Described in this unit is a protocol for consistently inducing arthritis in female Lewis rats by immunizing them with bovine type II collagen (CII) emulsified in complete Freund's adjuvant. This model is of value not only in defining the underlying pathogenesis of RA, but also as a tool for evaluating pharmacological strategies for treating this condition.Specific Antinociceptive Activity of Cholest-4-en-3-one, Oxime (TRO19622) in Experimental Models of Painful Diabetic and Chemotherapy-Induced NeuropathyThierry Bordet?·?Bruno Buisson?·?Magali Michaud?·?Jean-Louis Abitbol?·?Fabien Marchand?·?John Grist?· Emile Andriambeloson · HYPERLINK "" Marzia Malcangio?·?Rebecca M PrussJ Pharmacol Exp Ther.?2008 Aug;326(2):623-32. doi: 10.1124/jpet.108.139410. Epub 2008 May 20.Diabetes and cancer chemotherapies are often associated with painful neuropathy. The mechanisms underlying neuropathic pain remain poorly understood, and the current therapies have limited efficacy and are associated with dose-limiting side effects. We recently described the pharmacological characterization of cholest-4-en-3-one, oxime (TRO19622), a cholesterol-like compound, that significantly reduced axonal degeneration and accelerated recovery of motor nerve conduction in a model of peripheral neuropathy induced by crushing the sciatic nerve. These results triggered investigation of efficacy in other preclinical models of peripheral neuropathy. Here, we report evidence that daily oral administration of?TRO19622, while similarly improving motor nerve conduction impaired in streptozotocin-induced diabetic rats, also reversed neuropathic pain behavior as early as the first administration. Further exploration of these acute antinociceptive effects demonstrated that?TRO19622?was also able to reverse tactile allodynia in vincristine-treated rats, a model of chemotherapy-induced neuropathic pain. It is interesting to note that?TRO19622?did not have analgesic activity in animal models of pain produced by formalin injection, noxious thermal or mechanical stimulation, or chronic constriction injury of the sciatic nerve, indicating that painful diabetic or chemotherapy-induced neuropathies share a common mechanism that is distinct from acute, inflammationdriven, or lesion-induced neuropathic pain. These results support the potential use of?TRO19622?to treat painful diabetic and chemotherapy-induced neuropathies.Interleukin-6 protects against paclitaxel, cisplatin and vincristine-induced neuropathies without impairing chemotherapeutic activityNoelle Callizot?· Emile Andriambeloson ·?Jonathan Glass?·?Michel Revel?·?Pamela Ferro?·?Rocco Cirillo??Pierre-Alain Vitte?·?Michel DreanoCancer Chemother Pharmacol.?2008 Nov;62(6):995-1007. doi: 10.1007/s00280-008-0689-7. Epub 2008 Feb 13.PURPOSE: This study was conducted to investigate the potential neuroprotective effect of IL-6 on chemotherapy induced neuropathy (CIN). IL-6 was compared to four-methylcatechol (4-MC)-a known inducer of NGF secretion previously shown to exhibit neuroprotective effects in CIN models.METHODS: Three CIN models were used; two in rats (cisplatin and vincristine) and one in mice (paclitaxel). IL-6 was delivered in four different doses in rats (0.3, 1, 3, 10 microg/kg, sc) every day from the first day of chemotherapeutic agent intoxication until the end of the study (day 37 for cisplatin protocol and day 30 for vincristine procedure). In mice, IL-6 was delivered at 10 microg/kg, sc either daily or three times a week from the first day of intoxication until the end of the study (day 19). Behavioral testings (hot plate and rotarod), nerve conduction studies (CMAP, SNCV, H-wave) and histo-morphometric analysis were done for all models. In addition, we tested whether IL-6 interfered with the tumor-reducing effects of the chemotherapeutic agents.RESULTS: IL-6 treatment prevented the behavioral and electrophysiological abnormalities produced by vincristine, cisplatin and Taxol intoxication, and similarly prevented the pathological changes in peripheral nerves. The neuroprotective action of chronic IL-6 treatment was at least equal to that of 4-MC. In addition, IL-6 neither inhibited the antitumour activity of cisplatin, nor stimulated tumour growth.CONCLUSION: IL-6 at low doses (10 microg/kg) provided protection?against?the development of CIN without demonstrating interference with the anti tumoural activity of these anti-mitotic drugs.Interleukin-6 attenuates the development of experimental diabetes-related neuropathyEmile Andriambeloson ·?Caroline Baillet?·?Pierre-Alain Vitte?·?Gianni Garotta?·?Michel Dreano?·?Noelle CallizotNeuropathology.?2006 Feb;26(1):32-42.Neuropathy is the most severe and the least understood complication of diabetes. We investigated the potential neuroprotective effect of IL-6 therapy in an?experimental?model of diabetic neuropathy. A single i.v. injection of streptozotocin (STZ, 55 mg/kg) was used to induce?experimentaldiabetes in adult males. IL-6 (1, 10 or 30 microg/kg) was administrated either intraperitoneally on a daily basis or subcutaneously (s.c.) on a daily, on a three times or one time per week basis, starting at day 10 post-STZ. A decrease in sensory nerve conduction velocity (SNCV), indicative of neuropathy, is seen in STZ rats as early as day 10 post-STZ, a time at which blood glycaemia is already maximal. At later time points, this electrophysiological impairment became severe and clinically apparent by affecting tail flick latency. Motor dysfunction defined by a significant increase in compound muscle action potential (CMAP) latency was also recorded. At the completion of the study (day 40 post-STZ), histological examination revealed significant axonopathy and myelin loss, along with an increase in the proportion of fibers with abnormal appearance in sciatic nerves of STZ rats. These changes were not observed in non-diabetic rats and were significantly prevented by IL-6 treatment. The optimal dose appeared to be 10 microg/kg s.c. three injections per week, which showed a better effect in most of the parameters studied than 4-methylcatechol, a NGF-like neuroprotective compound. Once weekly and three times weekly administrations of IL-6 were as effective as daily treatment. Taken together, these results support the potential neuroprotective actions of IL-6. The fact that the half-life of IL-6 is only approximately 5 h while weekly dosing was neuroprotective strongly suggests activation by IL-6 of effector molecule(s) with longer duration of action.Article:?Functional maturation of nicotinic acetylcholine receptors as an indicator of murine muscular differentiation in a new nerve-muscle co-culture systemStéphanie Wagner ·?Olivier M Dorchies?·?Herrade Stoeckel?·?Jean-Marie Warter?·?Philippe Poindron?·Pflugers Arch.?2003 Oct;447(1):14-22. Epub 2003 Aug 28.Under normal conditions in situ, muscle fibers and motoneurons, the main partners of motor units, are strongly dependent on each other. This interdependence hinders ex vivo studies of neuromuscular disorders where nervous or muscular components are considered separately. To allow in vitro access to complex nerve-muscle relationships, we developed a novel nerve-muscle co-culture system where mouse muscle innervation is assured by rat spinal cord explants. The degree of muscular?maturation?during co-culture was evaluated using the distribution of?nicotinicacetylcholine?receptors (AChRs) and their electrophysiological characteristics before and after innervation. In myotubes from non-innervated cultures, AChRs were diffusely distributed over the entire myotube surface. Their single-channel conductance (33.5+/-0.6 pS) and mean open time (8.1+/-0.7 ms) are characteristic of AChRs described in embryonic or denervated skeletal muscles. In innervated muscle fibers from co-cultures, AChRs appear as discrete aggregates and co-localize with synaptotagmin. In addition to the embryonic type currents, in innervated fibers AChR currents having high conductance (53.3+/-5.9 pS) and short mean open time (2.6+/-0.1 ms), characteristic of AChRs at mature neuromuscular junctions, were observed. Our data support the use of this new nerve-muscle co-culture system as a reliable model for the study of murine muscular differentiation and function.Normal innervation and differentiation of X-linked myotubular myopathy muscle cells in a nerve-muscle coculture systemOlivier M Dorchies?·?Jocelyn Laporte?· Stéphanie Wagner ·?Colette Hindelang?·?J M Warter?·?J L Mandel?Neuromuscul Disord.?2001 Nov;11(8):736-46.To study the pathogenesis of X-linked recessive myotubular myopathy (XLMTM), we used a nerve-muscle coculture system which allows the reconstitution of functional motor units in vitro after coupling of human skeletal muscle cells with embryonic rat spinal cord explants. We used three skeletal muscle cell lines derived from subjects with known mutations in the MTM1 gene (two from embryonic tissues, associated with mutations predicted to give a severe phenotype, and one from a neonate still alive at 3 years 6 months and exhibiting a mild phenotype). We compared these three XLMTM muscle cell cultures with control cultures giving special attention to behaviour of living cocultures (formation of the myofibres, contractile activity, survival), expression of muscular markers (desmin, dystrophin, alpha-actinin, troponin-T, myosin heavy chain isoforms), and nerve-muscle interactions (expression and aggregation of the nicotinic acetylcholine receptors). We were unable to reproduce any 'myotubular' phenotype since XLMTM muscle cells behaved like normal cells with regard to all the investigated parameters. Our results suggest that XLMTM muscle might be intrinsically normal and emphasize the possible involvement of the myotubularin-deficient motor neurons in the development of the disease.POSTERSReversal effect of donepezil on cognitive impairment induced by cholinergic and glutamatergic antagonists in miceStéphanie Wagner?·?Etienne Poiraud?·?Bertrand Huyard?· Emile AndriambelosonA non-sedating dose of diazepam improves symptoms of panic anxiety disorder in the ratEmile Andriambeloson ·?Etienne Poiraud?·?Julien Bindler?·?Bertrand Huyard?·?Stéphanie WagnerSubchronic donepezil prevents amyloid-beta–induced memory disruption in the ratStéphanie Wagner?·?Etienne Poiraud?· Emile AndriambelosonEvaluation of dynamic weight bearing (gait) following unilateral sciatic nerve crush in the mouseStéphanie Wagner?·?Lucia Gorj?·?Julien Bindler?·?Etienne Poiraud?·Nassima Kadouci?· Emile AndriambelosonDexamethasone markedly reduces the clinical deficit in relapsing-remitting experimental autoimmune encephalomyelitis in the ratStéphanie Wagner?·?Julien Bindler?· Emile AndriambelosonP.4.d.001 BNC210 is a novel, fast acting compound with potent anxiolytic activity and no side effectsS. O'Connor?· E. Andriambeloson ·?B. Huyard?·?S. Wagner?·?B. Sleebs·?C. Bui?·?G. Kremmidiotis?·?B. FlynnBNC-210: A novel compound with potent anxiolytic activityE. Andriambeloson ·?S. Wagner?·?B. Huyard?·?B. Sleebs?·?N. Quasi?·?C. Bui?·?S. O'Connor?·?I. StreetP.2.h.001 The phospholipase C inhibitor U73122 inhibits the in vitro and in vivo activity of the novel anxiolytic and antidepressant compound BNC210S. O'Connor?· S. Wagner ·?B. Huyard?·?G. Kremmidiotis?·?E. AndriambelosonP.1.d.021 Evaluation of the novel anxiolytic compound BNC210 in a rodent model of cholecystokinin-induced panicS. O'Connor?·?B. Huyard?·?G. Kremmidiotis?· S. Wagner ·?E. AndriambelosonCharacterization of BNC375, a novel α7 nAChR positive allosteric modulator for the treatment of cognitive impairment in Alzheimer's diseaseA.A. Grishin?·?B. Huyard?·?C. Coles?·?P. Kolesik?·?Y. Kolev?· S. Wagner ·E. Anddriambeloson?·?A. Harvey?·?S. O’ConnorEvaluation of dynamic weight bearing (gait) following unilateral sciatic nerve crush in the mouseStéphanie Wagner ·?Lucia Gorj?·?Julien Bindler?·?Etienne Poiraud?·Nassima Kadouci?·?Emile AndriambelosonDexamethasone markedly reduces the clinical deficit in relapsing-remitting experimental autoimmune encephalomyelitis in the ratStéphanie Wagner ·?Julien Bindler?·?Emile AndriambelosonNON UTILISESTransplantation‐Induced Functional/Morphological Changes in Rat Aorta Allografts Differ from Those in Arteries of Rat Kidney AllograftsEmile Andriambeloson ·?Catherine Cannet?·?Charles Pally?·?Bernd Klanke?·?Christian Bruns?·?Hans-Günter Zerwes?·?Marc BigaudWine polyphenols stimulate superoxide anion production to promote calcium signaling and endothelial-dependent vasodilatationJ Duarte?· E Andriambeloson ·?M Diebolt?·?R AndriantsitohainaMacrophage labelling by SPIO as an early marker of allograft chronic rejection a rat model of kidney transplantationN Beckmann?·?C Cannet?·?M Fringeli-Tanner?·?D Baumann?·?C Pally?·C Bruns?·?H-G Zerwes?· E Andriambeloson ·?M BigaudRed wine polyphenols increase calcium in bovine aortic endothelial cells: A basis to elucidate signalling pathways leading to nitric oxide productionSophie Martin?· Emile Andriambeloson ·?Ken Takeda?·?Ramaroson AndriantsitohainaChemical regulation of nitric oxide: A role for intracellular myoglobin?Emile Andriambeloson ·?Paul K WittingTransplantation-induced endothelial dysfunction as studied in rat aorta allograftsEmile Andriambeloson ·?Charles Pally?·?Bastian Hengerer?·Catherine Cannet?·?Zariana Nikolova?·?Christian Bruns?·?H G Zerwes·?Marc BigaudSimultaneous transplantation model of the aorta and carotid in ratsZ.S. Chen?·?J Joergensen?· E AndriambelosonEndothelial dysfunction and denudation in rat aortic allograftsE Andriambeloson ·?M Bigaud?·?E O Schraa?·?T Kobel?·?V Lobstein?·?C Pally?·?H G ZerwesComplete loss of functional smooth muscle cells precedes vascular remodeling in rat aorta allograftsMarc Bigaud?·?Edo O. Schraa?· Emile Andriambeloson ·?Valerie Lobstein?·?Charles Pally?·?Tanja Kobel?·?Christian Bruns?·?Hans-Unter And?·?ZerwesEndothelial NO release caused by red wine polyphenolsJ C Stoclet?·?Kleschyov AL?· E Andriambeloson ·?M Diebolt?·?R AndriantsitohainaArticle:?Protection of dystrophic muscle cells with polyphenols from green tea correlates with improved glutathione balance and increased expression of 67LR, a receptor for (?)-epigallocatechin gallateOlivier M Dorchies?· Stéphanie Wagner ·?Timo M Buetler?·?Urs T RueggThe difficult-to-cultivate coxsackieviruses A can productively multiply in primary culture of mouse skeletal muscleSiwar Nsaibia?· Stéphanie Wagner ·?Philippe Rondé?·?Jean-Marie Warter?·?Philippe Poindron?·?Mahjoub Aouni?·?Olivier M DorchiesArticle:?Dorchies, OM, Wagner, S, Vuadens, O, Waldhauser, K, Buetler, TM, Kucera, P et al.. Green tea extract and its major polyphenol (-)-epigallocatechin gallate improve muscle function in a mouse model for Duchenne muscular dystrophy. Am J Physiol Cell Physiol 290: C616-C625Olivier M Dorchies?· Stéphanie Wagner ·?Ophélie Vuadens?·?Katri Waldhauser?·?Timo M Buetler?·?Pavel Kucera?·?Urs T RueggConference Paper:?Green tea polyphenols improve histology and mechanical properties of skeletal muscle in the mdx5Cv dystrophic mouseOM Dorchies?· S Wagner ·?TM Buetler?·?O Vuadens?·?P Kucera?·?UT RueggConference Paper:?Anti-fibrotic properties of green tea catechins on mouse muscle cell culturesOM Dorchies?· S Wagner ·?KM Waldhauser?·?TM Buetler?·?UT RueggConference Paper:?Antioxidant green tea catechins display differential protective effects on normal and dystrophic myotubes exposed to free radicalsOM Dorchies?· S Wagner ·?TM Buetler?·?UT RueggDifferential calcium sensitivity of primary cultured myotubes and muscle fibers derived from mdx and control miceS Rottet?·?O Basset?·?OM Dorchies?· S Wagner ·?L Gschwind?·?TM Buetler?·?UT RueggPharmacological control of cellular calcium handling in dystrophic skeletal muscle. Neuromuscular Disorders 12:S155-S161Urs T Ruegg?·?Valérie Nicolas-Métral?·?Corinne Challet?·?Katy Bernard-Hélary?·?Olivier M Dorchies?· Stéphanie Wagner ·?Timo M BuetlerConference Paper:?Mechanism of nitric oxide production by wine polyphenols in bovine aortic endothelial cellsAndriambeloson E. ·?Duarte J.?·?Kleschyov A. L.?·?Stoclet J.-C?· HYPERLINK "" Andriantsitohaina R ................
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