首页 | 本学科首页   官方微博 | 高级检索  
检索        


mGlu1 and mGlu5 receptor antagonists lack anticonvulsant efficacy in rodent models of difficult-to-treat partial epilepsy
Authors:Löscher Wolfgang  Dekundy Andrzej  Nagel Jens  Danysz Wojciech  Parsons Chris G  Potschka Heidrun
Institution:

aDepartment of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany

bIn Vivo Pharmacology, Preclinical Research and Development, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

cIn Vitro Pharmacology, Preclinical Research and Development, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

Abstract:Modulation of metabotropic glutamate (mGlu) receptors represents an interesting new approach for the treatment of a range of neurological and psychiatric disorders. Several lines of evidence suggest that functional blockade of group I (mGlu1 and mGlu5) receptors may be beneficial for treatment of epileptic seizures. This study was conducted to investigate whether mGlu1 or mGlu5 receptor antagonists have the potential to block partial or secondarily generalized seizures as occurring in partial epilepsy, the most common and difficult-to-treat type of epilepsy in patients. For this purpose, we systemically administered novel highly selective and brain penetrable group I mGlu receptor antagonists, i.e., the mGlu1 receptor antagonist EMQMCM 3-ethyl-2-methyl-quinolin-6-yl-(4-methoxy-cyclohexyl)-methanone methanesulfonate] and the mGlu5 receptor antagonist MTEP ((2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), at doses appropriate for mGlu1 or mGlu5 receptor-mediated effects in rodent models of partial seizures. Two models were used: the 6-Hz electroshock model of partial seizures in mice and the amygdala-kindling model in rats. Clinically established antiepileptic drugs were included in the experiments for comparison. Antiepileptic drugs exerted significant anticonvulsant effects in both models, while EMQMCM and MTEP were ineffective in this regard, although both compounds were administered up to doses associated with essentially full receptor occupancy and with typical mGlu receptor-mediated effects in rodent models of anxiety or pain. Brain microdialysis for determining extracellular levels of MTEP following i.p. administration in rats substantiated that effective brain concentrations were reached at times of our experiments in seizure models. The present results do not support a significant anticonvulsant potential of group I mGlu receptor antagonists in rodent models of difficult-to-treat partial epilepsy.
Keywords:Metabotropic glutamate receptors  Epilepsy  Antiepileptic drugs  Kindling
本文献已被 ScienceDirect PubMed 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号