PDF(Pubmed)
Abstract：
Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy. Fenamates are unique because they are both non-steroidal anti-inflammatory drugs (NSAIDs) and highly subunit selective modulators of GABAA receptors. In the current study we have investigated the hypothesis that fenamates have antiseizure properties using mature human stem cell-derived neuro-glia cell cultures, maintained in long-term culture, and previously shown to be sensitive to first, second and third generation antiepileptics. Mefenamic acid, flufenamic acid, meclofenamic acid, niflumic acid, and tolfenamic acid (each tested at 10-100 μM) attenuated 4-aminopyridine (4-AP, 100 μM) evoked epileptiform activity in a dose-dependent fashion. These actions were as effective diazepam (3-30 μM) and up to 200 times more potent than phenobarbital (300-1,000 μM). The low (micromolar) concentrations of fenamates that inhibited 4-AP evoked epileptiform activity correspond to those reported to potentiate GABAA receptor function. In contrast, the fenamates had no effect on neural spike amplitudes, indicating that their antiseizure actions did not result from inhibition of sodium-channels. The antiseizure actions of fenamates were also not replicated by either of the two non-fenamate NSAIDs, ibuprofen (10-100 μM) or indomethacin (10-100 μM), indicating that inhibition of cyclooxygenases is not the mechanism through which fenamates have anticonvulsant properties. This study therefore shows for the first time, using functionally mature human stem cell-derived neuroglial circuits, that fenamate NSAIDs have powerful antiseizure actions independent of, and in addition to their well-established anti-inflammatory properties, suggesting these drugs may provide a novel insight and new approach to the treatment of epilepsy in the future.
摘要：
癫痫中反复和不受控制的癫痫发作导致脑细胞损失和神经炎症。目前的抗惊厥药主要针对与癫痫发作活动有关的离子通道和受体。鉴定可抑制癫痫样活性并减少脑中炎症的神经治疗剂可在癫痫的长期管理中提供显著益处。Fenamates是独特的，因为它们既是非类固醇抗炎药（NSAID）又是GABAA受体的高度亚基选择性调节剂。在当前的研究中，我们已经调查了使用成熟的人类干细胞衍生的神经胶质细胞培养物具有抗癫痫特性的假设，保持在长期文化中，之前被证明对第一敏感，第二代和第三代抗癫痫药。甲芬那酸,氟芬那酸,甲氯芬那酸,尼氟丁酸,和托芬那酸（每种在10-100μM下测试）减毒4-氨基吡啶（4-AP，100μM）以剂量依赖性方式诱发的癫痫样活动。这些作用与地西泮（3-30μM）一样有效，比苯巴比妥（300-1,000μM）的效力高200倍。抑制4-AP诱发的癫痫样活性的低（微摩尔）浓度的fenamate与报道的增强GABAA受体功能的那些相对应。相比之下,fenamates对神经尖峰幅度没有影响，表明它们的抗癫痫作用不是由于钠通道的抑制。非芬酸盐的抗癫痫作用也未被两种非芬酸盐NSAIDs复制，布洛芬（10-100μM）或吲哚美辛（10-100μM），这表明环加氧酶的抑制不是fenamates具有抗惊厥特性的机制。因此，这项研究首次表明，使用功能成熟的人类干细胞衍生的神经胶质回路，非芬酯NSAIDs具有强大的抗癫痫作用，除了它们公认的抗炎特性，这表明这些药物可能为未来癫痫的治疗提供新的见解和新的方法。
