Department of Pediatric Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China.
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Mol Neurobiol. 2018 Aug;38(6):1215-1226. doi: 10.1007/s10571-018-0586-5. Epub 2018 May 10.
Febrile seizure (FS) counts as the most common seizures symptom in children undergoing recurrent seizures, posing a high risk to developing subsequent temporal lobe epilepsy. Canonical transient receptor potential channel (TRPC) members are identified as the FS-related genes in hyperthermia prone rats. However, the role of TRPC3 in hyperthermia-induced FS rats remains unclear. In the present study, we investigated whether TRPC3 functionally contributes to the development of FSs. Elevated TRPC3 mRNA and protein levels was detected in hyperthermia-induced FS rats and rat hippocampal neuron cells. The specific inhibitor of TRPC3, Pyr3, remarkably attenuated the susceptibility and severity of seizures, neuronal cell death, and neuroinflammation in FS rats. Conversely, NCX3 activation was apparently suppressed in rats subjected to recurrent FS and rat hippocampal neuron cells. The expression of NCX3 was up-regulated after TRPC3 inhibition in vivo and in vitro. Furthermore, an interaction between TRPC3 and NCX3 was detected by co-immunoprecipitation. Inhibition of TRPC3 suppressed intracellular Ca levels in hyperthermia-treated hippocampal neuronal cells. In conclusion, our findings supported that TRPC3 functions as a critical regulator of seizure susceptibility and targeting TRPC3 may be a new therapeutic strategy for FS.
热性惊厥 (FS) 是儿童反复发作性惊厥中最常见的惊厥症状，存在发展为后续颞叶癫痫的高风险。经典瞬时受体电位通道 (TRPC) 成员被鉴定为热敏性大鼠 FS 相关基因。然而，TRPC3 在发热诱导的 FS 大鼠中的作用尚不清楚。在本研究中，我们研究了 TRPC3 是否在 FS 发作的发展中具有功能作用。在发热诱导的 FS 大鼠和大鼠海马神经元细胞中检测到 TRPC3 mRNA 和蛋白水平升高。TRPC3 的特异性抑制剂 Pyr3 显著减轻了 FS 大鼠的易感性和癫痫发作的严重程度、神经元细胞死亡和神经炎症。相反，在反复 FS 大鼠和大鼠海马神经元细胞中，NCX3 的激活明显受到抑制。TRPC3 抑制后，NCX3 的表达在体内和体外均上调。此外，通过共免疫沉淀检测到 TRPC3 和 NCX3 之间存在相互作用。TRPC3 抑制可降低发热处理的海马神经元细胞内的 Ca 水平。总之，我们的研究结果支持 TRPC3 作为惊厥易感性的关键调节因子的作用，靶向 TRPC3 可能是 FS 的一种新的治疗策略。
