Laboratory Animal Center, Xuzhou Medical University, Xuzhou 221004, Jiangsu, PR China.
Laboratory Animal Center, Xuzhou Medical University, Xuzhou 221004, Jiangsu, PR China; Institute of Cellular and Molecular Biology, School of Life Science, Jiangsu Normal University, Xuzhou 221004, Jiangsu, PR China.
Brain Res. 2022 Jun 15;1785:147881. doi: 10.1016/j.brainres.2022.147881. Epub 2022 Mar 10.
Epileptogenesis is a dynamic process accompanied by the hippocampal neuroinflammation, aberrant neurogenesis and cognitive decline. Accordingly, anti-neuroinflammation and neuroprotective therapy may be considered in effective prophylaxis and therapeutics for epilepsy. Insulin-like growth factor-1 (IGF-1) is well acknowledged as a neuroprotective factor to promote neurogenesis and neuronal survival and synaptogenesis, wherein there has been controversy as to its implication in epilepsy. In our prior experiments, we established transgenic mice with overexpressed IGF-1 specifically in neural stem cells (NSCs). This experiment sought to investigate the implications of overexpressed IGF-1 in a PTZ-induced mouse model of chronic epilepsy. Herein we demonstrated that increasing hippocampal levels of IGF-1 sufficed to exhibit long-term anti-epileptogenesis effect on epileptic mouse model. The severity of epilepsy was assessed with onset latency, Racine score, percentage of mice with stage IV-V seizures, duration of seizures. Strikingly, IGF-1 transgenic mice showed more lessened severity than the wild-type (W-T) mice. Moreover, IGF-1 transgenic mice exhibited a lesser population of IBA-1-positive cells in CA1 of hippocampus than did W-T mice in the chronic phase, with a significant downregulation of IL-1β, IL-6, and TNF-α in hippocampus, indicating that IGF-1 overexpression significantly mitigated inflammation in the hippocampus. In addition, Nissl staining revealed a greater population of viable neurons in CA1 of IGF-1 transgenic mice versus the W-T mice. TUNEL staining and western blotting indicated fewer apoptotic cells in transgenic mice. Moreover, we identified the evident increase in BrdU-positive and DCX-positive cell populations in dentate gyrus (DG) in IGF-1 transgenic mice, versus the W-T mice, indicative of the role of IGF-1 overexpression in promoting long-term hippocampal neurogenesis in the chronic phase of epilepsy. Collectively, our data authenticated the neuroprotective and antiinflammatory effects of IGF-1 in the chronic phase of epilepsy, which may benefit the long-term anti-epileptogenesis regimens.
癫痫发生是一个伴随海马神经炎症、异常神经发生和认知能力下降的动态过程。因此，抗神经炎症和神经保护治疗可能被认为是癫痫有效预防和治疗的方法。胰岛素样生长因子-1（IGF-1）是一种公认的神经保护因子，可促进神经发生、神经元存活和突触形成，但其在癫痫中的作用存在争议。在我们之前的实验中，我们建立了神经干细胞（NSCs）中 IGF-1 过表达的转基因小鼠。本实验旨在研究过表达 IGF-1 在匹罗卡品诱导的慢性癫痫小鼠模型中的意义。结果表明，增加海马 IGF-1 水平足以对癫痫模型小鼠产生长期抗癫痫发生作用。采用发作潜伏期、Racine 评分、出现 4-5 级发作的小鼠百分比、发作持续时间来评估癫痫严重程度。值得注意的是，IGF-1 转基因小鼠的严重程度比野生型（W-T）小鼠明显减轻。此外，与 W-T 小鼠相比，IGF-1 转基因小鼠在慢性期海马 CA1 区的 IBA-1 阳性细胞数量较少，海马组织中 IL-1β、IL-6 和 TNF-α 的表达水平显著下调，表明 IGF-1 过表达显著减轻了海马组织的炎症反应。此外，尼氏染色显示 IGF-1 转基因小鼠海马 CA1 区存活神经元数量较多。TUNEL 染色和 Western blot 显示转基因小鼠凋亡细胞较少。此外，我们发现 IGF-1 转基因小鼠齿状回（DG）中 BrdU 阳性和 DCX 阳性细胞数量明显增加，提示 IGF-1 过表达在促进慢性期癫痫的长期海马神经发生中起作用。综上所述，我们的数据证实了 IGF-1 在癫痫慢性期的神经保护和抗炎作用，这可能有益于长期抗癫痫发生方案。
