Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.
Department of Medical Science, College of Medicine, Hallym University, Chuncheon 24252, Korea.
Int J Mol Sci. 2017 Nov 2;18(11):2311. doi: 10.3390/ijms18112311.
Epileptic seizures are short episodes of abnormal brain electrical activity. Many survivors of severe epilepsy display delayed neuronal death and permanent cognitive impairment. Donepezil is an acetylcholinesterase inhibitor and is an effective treatment agent for Alzheimer's disease. However, the role of donepezil in seizure-induced hippocampal injury remains untested. Temporal lobe epilepsy (TLE) was induced by intraperitoneal injection of pilocarpine (25 mg/kg). Donepezil (2.5 mg/kg/day) was administered by gavage in three different settings: (1) pretreatment for three days before the seizure; (2) for one week immediately after the seizure; and (3) for three weeks from three weeks after the seizure. We found that donepezil showed mixed effects on seizure-induced brain injury, which were dependent on the treatment schedule. Pretreatment with donepezil aggravated neuronal death, oxidative injury, and microglia activation. Early treatment with donepezil for one week showed neither adverse nor beneficial effects; however, a treatment duration of three weeks starting three weeks after the seizure showed a significant reduction in neuronal death, oxidative injury, and microglia activation. In conclusion, donepezil has therapeutic effects when injected for three weeks after seizure activity subsides. Therefore, the present study suggests that the therapeutic use of donepezil for epilepsy patients requires a well-conceived strategy for administration.
癫痫发作是大脑电活动的短暂异常。许多严重癫痫幸存者表现出神经元延迟死亡和永久性认知障碍。多奈哌齐是一种乙酰胆碱酯酶抑制剂，是阿尔茨海默病的有效治疗药物。然而，多奈哌齐在癫痫诱导的海马损伤中的作用尚未得到检验。颞叶癫痫（TLE）通过腹腔注射匹鲁卡品（25mg/kg）诱导。多奈哌齐（2.5mg/kg/天）通过灌胃在三种不同的情况下给药：（1）在癫痫发作前三天预处理；（2）在癫痫发作后立即进行一周治疗；（3）在癫痫发作后三周内进行三周治疗。我们发现多奈哌齐对癫痫诱导的脑损伤有混合作用，这取决于治疗方案。预处理多奈哌齐加重神经元死亡、氧化损伤和小胶质细胞激活。早期治疗一周内多奈哌齐既没有不良也没有有益的影响；然而，从癫痫发作后三周开始的三周治疗显示神经元死亡、氧化损伤和小胶质细胞激活显著减少。总之，癫痫发作活动消退后注射多奈哌齐三周具有治疗效果。因此，本研究表明，对癫痫患者使用多奈哌齐需要精心设计的给药策略。
