Löscher Wolfgang, Dekundy Andrzej, Nagel Jens, Danysz Wojciech, Parsons Chris G, Potschka Heidrun
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, D-30559 Hannover, Germany.
Neuropharmacology. 2006 Jun;50(8):1006-15. doi: 10.1016/j.neuropharm.2006.02.001. Epub 2006 Mar 24.
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.
代谢型谷氨酸（mGlu）受体的调节代表了一种用于治疗一系列神经和精神疾病的有趣新方法。多项证据表明，I组（mGlu1和mGlu5）受体的功能阻断可能对癫痫发作的治疗有益。本研究旨在调查mGlu1或mGlu5受体拮抗剂是否有可能阻断部分性癫痫（患者中最常见且最难治疗的癫痫类型）中出现的部分性或继发性全身性癫痫发作。为此，我们系统地给予了新型高选择性且可穿透脑的I组mGlu受体拮抗剂，即mGlu1受体拮抗剂EMQMCM [3-乙基-2-甲基喹啉-6-基-（4-甲氧基环己基）甲酮甲磺酸盐]和mGlu5受体拮抗剂MTEP（[(2-甲基-1,3-噻唑-4-基）乙炔基]吡啶），剂量适合于在部分性癫痫发作的啮齿动物模型中产生mGlu1或mGlu5受体介导的效应。使用了两种模型：小鼠部分性癫痫发作的6 Hz电休克模型和大鼠杏仁核点燃模型。实验中纳入了临床已确立的抗癫痫药物进行比较。抗癫痫药物在两种模型中均发挥了显著的抗惊厥作用，而EMQMCM和MTEP在这方面无效，尽管两种化合物的给药剂量高达与在啮齿动物焦虑或疼痛模型中基本完全占据受体以及典型的mGlu受体介导效应相关的剂量。在大鼠腹腔注射后通过脑微透析测定细胞外MTEP水平，证实了在我们癫痫发作模型实验时达到了有效的脑浓度。目前的结果不支持I组mGlu受体拮抗剂在难治性部分性癫痫的啮齿动物模型中具有显著抗惊厥潜力的观点。
