Predicting signaling pathways regulating demyelination in a rat model of lithium-pilocarpine-induced acute epilepsy: A proteomics study
Predicting signaling pathways regulating demyelination in a rat model of lithium-pilocarpine-induced acute epilepsy: A proteomics study
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DOI：
10.1016/j.ijbiomac.2021.10.209
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发表时间：
2021-12-09
影响因子：
8.2
通讯作者：
Tao, Sun
中科院分区：
文献类型：
--
作者：
Wang, Peng;Ma, Kang;Tao, Sun
在难治性癫痫（IE）的动物模型中观察到脱髓鞘。癫痫发生损害髓鞘并使少突胶质细胞前体细胞（OPC）发育失调。然而，癫痫脱髓鞘的分子调控途径尚不清楚。在这里，我们预测了在锂-盐酸匹罗卡品诱导的癫痫大鼠模型中调节脱髓鞘的分子机制。我们确定DGKA/Mboat 2/Inpp 5 j和NOS/角蛋白28是通过甘油脂质和甘油磷脂代谢、磷脂酰肌醇信号传导和脱髓鞘前脑切片培养物（FSC）中的雌激素信号传导来调节脱髓鞘的主要靶分子。在类神经纤维样FCS中，Cnp和MBP通过Pak 4/Tmsb 4x（也称为T β 4）和Kif 5c/Kntc 1调节肌动蛋白细胞骨架。T β 4可能通过p38 MAPK/ERK 1/JNK 1途径抑制OPC分化成熟和MBP磷酸化。MAPK信号通路在髓鞘样FCS中比在脱髓鞘FCS中更可能被激活。盐酸匹罗卡品诱导的急性癫痫大鼠海马pMBP表达减少。锂-盐酸匹罗卡品致痫大鼠海马和胼胝体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，T β 4和MAPK信号通路调节癫痫大鼠模型海马中pMBP的减少。我们的研究结果表明，调节肌动蛋白细胞骨架，T β 4和MAPK信号通路可能有助于预防IE的脱髓鞘。
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 T beta 4) and Kif5c/Kntc1. T beta 4 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 remyelinationrelated factors was suppressed in the hippocampus and corpus callosum in lithium-pilocarpine hydrochlorideinduced epilepsy rats. These findings suggest that the actin cytoskeleton, T beta 4, 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, T beta 4, and MAPK signaling pathways may facilitate the prevention of demyelination in IE.