Department of Neurophysiology and Neuropharmacology, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China.
Mol Neurobiol. 2020 Nov;57(11):4810-4824. doi: 10.1007/s12035-020-02060-8. Epub 2020 Aug 15.
Disruption of remyelination contributes to neurodegeneration and cognitive impairment in chronically disabled patients. Valproic acid (VPA) inhibits histone deacetylase (HDAC) function and probably promotes oligodendrocyte progenitor cell (OPC) proliferation and differentiation; however, the relevant molecular mechanisms remain unknown. Here, focal demyelinating lesions (FDLs) were generated in mice by two-point stereotactic injection of lysophosphatidylcholine (LPC) into the corpus callosum. Cognitive functions, sensorimotor abilities and histopathological changes were assessed for up to 28 days post-injury with or without VPA treatment. Primary OPCs were harvested and used to study the effect of VPA on OPC differentiation under inflammatory conditions. VPA dose-dependently attenuated learning and memory deficits and robustly protected white matter after FDL induction, as demonstrated by reductions in SMI-32 and increases in myelin basic protein staining. VPA also promoted OPC proliferation and differentiation and increased subsequent remyelination efficiency by day 28 post-FDL induction. VPA treatment did not affect HDAC1, HDAC2 or HDAC8 expression but reduced HDAC3 protein levels. In vitro, VPA improved the survival of mouse OPCs and promoted their differentiation into oligodendrocytes following lipopolysaccharide (LPS) stimulation. LPS caused OPCs to overexpress HDAC3, which translocated from the cytoplasm into the nucleus, where it directly interacted with the nuclear transcription factor PPAR-γ and negatively regulated PPAR-γ expression. VPA decreased the expression of HDAC3 and promoted remyelination and functional neurological recovery after FDL. These findings may support the use of strategies modulating HDAC3-mediated regulation of protein acetylation for the treatment of demyelination-related cognitive dysfunction.
髓鞘修复障碍导致慢性残疾患者的神经退行性变和认知障碍。丙戊酸（VPA）抑制组蛋白去乙酰化酶（HDAC）的功能，可能促进少突胶质前体细胞（OPC）的增殖和分化；然而，相关的分子机制尚不清楚。本研究通过两点立体定位将溶血磷脂酰胆碱（LPC）注射到胼胝体中，在小鼠中产生局灶性脱髓鞘病变（FDL）。在损伤后长达 28 天，用或不用 VPA 治疗，评估认知功能、感觉运动能力和组织病理学变化。收获原代 OPC 并用于研究 VPA 在炎症条件下对 OPC 分化的影响。VPA 剂量依赖性地减轻了 FDL 诱导后的学习和记忆障碍，并强烈保护了白质，表现为 SMI-32 的减少和髓鞘碱性蛋白染色的增加。VPA 还促进了 OPC 的增殖和分化，并增加了 FDL 诱导后 28 天的后续髓鞘再生效率。VPA 治疗不影响 HDAC1、HDAC2 或 HDAC8 的表达，但降低了 HDAC3 蛋白水平。在体外，VPA 改善了小鼠 OPC 的存活，并在脂多糖（LPS）刺激下促进了它们向少突胶质细胞的分化。LPS 导致 OPC 过度表达 HDAC3，其从细胞质转位到细胞核，在细胞核中与核转录因子 PPAR-γ 直接相互作用，并负调控 PPAR-γ 的表达。VPA 降低了 HDAC3 的表达，并促进了 FDL 后的髓鞘再生和神经功能恢复。这些发现可能支持使用调节组蛋白去乙酰化酶 3 介导的蛋白质乙酰化调节的策略来治疗与脱髓鞘相关的认知功能障碍。
