Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan 750004, China.
Department of Anatomy, Ningxia Medical University, Yinchuan 750004, China.
Int J Biol Macromol. 2021 Dec 15;193(Pt B):1457-1470. doi: 10.1016/j.ijbiomac.2021.10.209. Epub 2021 Nov 3.
Demyelination is observed in animal models of intractable epilepsy (IE). Epileptogenesis damages the myelin sheath and dysregulates oligodendrocyte precursor cell (OPC) development. However, the molecular pathways regulating demyelination in epilepsy are unclear. Here, we predicted the molecular mechanisms regulating demyelination in a rat model of lithium-pilocarpine hydrochloride-induced epilepsy. We identified DGKA/Mboat2/Inpp5j and NOS/Keratin 28 as the main target molecules that regulate demyelination via glycerolipid and glycerophospholipid metabolism, phosphatidylinositol signaling, and estrogen signaling in demyelinated forebrain slice cultures (FSCs). In seizure-like FCSs, the actin cytoskeleton was regulated by Cnp and MBP via Pak4/Tmsb4x (also known as Tβ4) and Kif5c/Kntc1. Tβ4 possibly prevented OPC differentiation and maturation and inhibited MBP phosphorylation via the p38MAPK/ERK1/JNK1 pathway. The MAPK signaling pathway was more likely activated in seizure-like FCSs than in demyelinated FCSs. pMBP expression was decreased in the hippocampus of lithium-pilocarpine hydrochloride-induced acute epilepsy rats. The expression of remyelination-related factors was suppressed in the hippocampus and corpus callosum in lithium-pilocarpine hydrochloride-induced epilepsy rats. These findings suggest that the actin cytoskeleton, Tβ4, and MAPK signaling pathways regulate the decrease in pMBP in the hippocampus in a rat model of epilepsy. Our results indicate that regulating the actin cytoskeleton, Tβ4, and MAPK signaling pathways may facilitate the prevention of demyelination in IE.
脱髓鞘可见于难治性癫痫（IE）的动物模型中。癫痫发生导致髓鞘损伤并使少突胶质前体细胞（OPC）发育失调。然而，调节癫痫中脱髓鞘的分子途径尚不清楚。在这里，我们预测了锂-匹鲁卡品盐酸盐诱导癫痫大鼠模型中调节脱髓鞘的分子机制。我们确定了 DGKA/Mboat2/Inpp5j 和 NOS/Keratin 28 作为主要靶分子，通过甘油脂质和甘油磷脂代谢、磷脂酰肌醇信号转导和雌激素信号转导调节脱髓鞘前脑切片培养物（FSCs）中的脱髓鞘。在癫痫样 FCS 中，肌动蛋白细胞骨架通过 Cnp 和 MBP 调节 Pak4/Tmsb4x（也称为 Tβ4）和 Kif5c/Kntc1。Tβ4 可能通过 p38MAPK/ERK1/JNK1 途径防止 OPC 分化和成熟并抑制 MBP 磷酸化。MAPK 信号通路在癫痫样 FCS 中比在脱髓鞘 FCS 中更可能被激活。在锂-匹鲁卡品盐酸盐诱导的急性癫痫大鼠海马中 pMBP 的表达减少。在锂-匹鲁卡品盐酸盐诱导的癫痫大鼠海马和胼胝体中，髓鞘再生相关因子的表达受到抑制。这些发现表明，肌动蛋白细胞骨架、Tβ4 和 MAPK 信号通路调节癫痫大鼠海马中 pMBP 的减少。我们的结果表明，调节肌动蛋白细胞骨架、Tβ4 和 MAPK 信号通路可能有助于预防 IE 中的脱髓鞘。
