Endocannabinoids block, status epilepticus in cultured hippocampal neurons
Endocannabinoids block, status epilepticus in cultured hippocampal neurons
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DOI：
10.1016/j.ejphar.2006.11.030
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发表时间：
2007-03-06
影响因子：
5
通讯作者：
DeLorenzo, Robert J.
中科院分区：
文献类型：
--
作者：
Deshpande, Laxmikant S.;Blair, Robert E.;DeLorenzo, Robert J.
癫痫持续状态是一种严重的神经系统疾病，具有显著的发病率和死亡率。抗癫痫药物如地西泮、苯巴比妥和苯妥英是癫痫持续状态治疗的主要药物。然而，超过20%的癫痫持续状态病例对使用两种或更多种抗癫痫药物的初始治疗是难治的。内源性大麻素被认为在调节癫痫发作活动和癫痫发作终止中起重要作用。本研究评价了主要内源性大麻素甲满和2-花生四烯酸甘油（2-AG）对低镁海马神经元培养模型中癫痫持续状态的影响。该模型中的癫痫持续状态对苯巴比妥和苯妥英治疗具有耐药性。Methanandamide和2-AG以剂量依赖性方式抑制癫痫持续状态，EC 50分别为145 +/- 4.15 nM和1.68 +/- 0.19 μ M。此外，甲雄胺和2-AG的抗癫痫持续状态作用是由大麻素CB 1受体的激活介导的，因为它们被大麻素CB 1受体拮抗剂AM 251阻断。这些结果提供了第一个证据表明，内源性大麻素，methanandamide和2-AG，是有效的抑制剂难治性癫痫持续状态在海马神经元培养模型，并表明，调节内源性大麻素系统可以提供一种新的治疗方法，用于治疗难治性癫痫持续状态。(c)2006 Elsevier B. V.保留所有权利。
Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg2+ hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC50 of 145 +/- 4.15 nM and 1.68 +/- 0.19 mu M, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB1 receptor since they were blocked by the cannabinoid CB1 receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus. (c) 2006 Elsevier B.V. All rights reserved.