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.

髓鞘再生中断导致慢性残疾患者的神经变性和认知障碍。丙戊酸（VPA）抑制组蛋白脱乙酰基酶（HDAC）的功能，并可能促进少突胶质祖细胞（OPC）的增殖和分化；然而，相关的分子机制仍然未知。在这里，通过将溶血磷脂酰胆碱（LPC）两点立体定向注射到call体中，在小鼠中产生了局灶性脱髓鞘病变（FDL）。在有或没有使用VPA治疗的情况下，对损伤后长达28天的认知功能，感觉运动能力和组织病理学变化进行了评估。收集初级OPC，并用于研究VPA对炎症条件下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，并保护了白质，如SMI-32减少和髓鞘碱性蛋白染色增加所证明。VPA还促进了FPC的增殖和分化，并在FDL诱导后第28天提高了随后的髓鞘再生效率。VPA处理不会影响HDAC1，HDAC2或HDAC8的表达，但会降低HDAC3的蛋白水平。在体外，VPA改善了小鼠OPC的存活，并促进了脂多糖（LPS）刺激后它们分化为少突胶质细胞。LPS导致OPC过表达HDAC3，HDAC3从细胞质转移到细胞核中，在该细胞中它直接与核转录因子PPAR-γ相互作用并且对PPAR-γ的表达负调控。VPA降低FDL后HDAC3的表达并促进髓鞘再生和功能神经恢复。这些发现可能支持使用调节HDAC3介导的蛋白质乙酰化调节策略来治疗脱髓鞘相关的认知功能障碍。