Phelan Kevin D, Shwe U Thaung, Cozart Michael A, Wu Hong, Mock Matthew M, Abramowitz Joel, Birnbaumer Lutz, Zheng Fang
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
Epilepsia. 2017 Feb;58(2):247-254. doi: 10.1111/epi.13648. Epub 2016 Dec 24.
Canonical transient receptor potential (TRPC) channels constitute a family of cation channels that exhibit a regional and cell-specific expression pattern throughout the brain. It has been reported previously that TRPC3 channels are effectors of the brain-derived neurotrophic factor (BDNF)/trkB signaling pathway. Given the long postulated role of BDNF in epileptogenesis, TRPC3 channels may be a critical component in the underlying pathophysiology of seizure and epilepsy. In this study, we investigated the precise role of TRPC3 channels in pilocarpine-induced status epilepticus (SE).
The role of TRPC3 channels was investigated using TRPC3 knockout (KO) mice and TRPC3-selective inhibitor Pyr3. Video and electroencephalography (EEG) recording of pilocarpine-induced seizures were performed.
We found that genetic ablation of TRPC3 channels reduces behavioral manifestations of seizures and the root-mean-square (RMS) power of SE, indicating a significant contribution of TRPC3 channels to pilocarpine-induced SE. Furthermore, the reduction in SE in TRPC3KO mice is caused by a selective attenuation of pilocarpine-induced theta activity, which dominates both the preictal phase and SE phase. Pyr3 also caused a reduction in the overall RMS power of pilocarpine-induced SE and a selective reduction in the theta activity during SE.
Our results demonstrate that TRPC3 channels unequivocally contribute to pilocarpine-induced SE and could be a novel molecular target for new anticonvulsive drugs.
经典瞬时受体电位（TRPC）通道构成了一类阳离子通道家族，在整个大脑中呈现出区域和细胞特异性的表达模式。先前已有报道称，TRPC3通道是脑源性神经营养因子（BDNF）/trkB信号通路的效应器。鉴于BDNF在癫痫发生中早已被假定的作用，TRPC3通道可能是癫痫发作和癫痫潜在病理生理学中的关键组成部分。在本研究中，我们调查了TRPC3通道在毛果芸香碱诱导的癫痫持续状态（SE）中的精确作用。
使用TRPC3基因敲除（KO）小鼠和TRPC3选择性抑制剂Pyr3来研究TRPC3通道的作用。对毛果芸香碱诱导的癫痫发作进行视频和脑电图（EEG）记录。
我们发现，TRPC3通道的基因缺失减少了癫痫发作的行为表现以及SE的均方根（RMS）功率，表明TRPC3通道对毛果芸香碱诱导的SE有显著贡献。此外，TRPC3基因敲除小鼠中SE的减少是由毛果芸香碱诱导的θ活动的选择性减弱引起的，θ活动在发作前期和SE期均占主导。Pyr3也导致毛果芸香碱诱导的SE的总体RMS功率降低以及SE期间θ活动的选择性降低。
我们的结果表明，TRPC3通道明确地促成了毛果芸香碱诱导的SE，并且可能是新型抗惊厥药物的新分子靶点。
