Abstract
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.
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Acknowledgements
This work was supported by the Chinese Natural Science Foundation (Grants 81873924, 81471257) and sponsored by Nantong Science and Technology Project (MS12018030, MS12018048). Dr. Wang’s work has also been funded by Qing Lan Project of Jiangsu Province of China.
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G.H.W. and Z.L.J. conceived, organized and supervised the work; L.Z.D., J.M.Z. and L.S.Y. performed the experiments; Y.C.S., D.Q.G., L.H.X. and Q.Q.L. contributed to the analysis of data; G.H.W. prepared, wrote and revised the manuscript.
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All experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Animal Ethics Committees of Nantong University (NU-2017-39).
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Fig. S1
Effect of VPA on spatial exploration and emotion in mice after FDL induction. (A) Proportions of time spent by mice exploring the novel object vs. both objects (RI values) in the novel object recognition test. (B–C) Results of the Y-maze test, (D–F) open-field test and (G) rotarod test performed 10 days after FDL induction. (H–I) Results of the Y-maze test performed 28 days after FDL induction. The data are presented as the means ± SEMs, n ≥ 8 mice/group. *p < 0.05 and **p < 0.01 for the indicated comparisons. (PNG 926 kb)
Fig. S2
Microarray analysis of the effect of VPA on the differentiation of primary cultured OPCs into oligodendrocytes after treatment with LPS in vitro. Gene-chip microarray analyses were performed using OPCs treated with vehicle, VPA (1 mM), LPS (5 μg/ml) or LPS + VPA for 24 h. The table lists several functional genes that showed at least 9-fold changes after VPA treatment based on two independent microarray assays. Interestingly, PPAR-γ, but not PPAR-α or PPAR-β, was upregulated by VPA. PPAR-γ is a transcription factor that regulates over 100 genes involved in inflammation, cell proliferation and differentiation. (PNG 1150 kb)
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Ding, L., Zhou, J., Ye, L. et al. PPAR-γ Is Critical for HDAC3-Mediated Control of Oligodendrocyte Progenitor Cell Proliferation and Differentiation after Focal Demyelination. Mol Neurobiol 57, 4810–4824 (2020). https://doi.org/10.1007/s12035-020-02060-8
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DOI: https://doi.org/10.1007/s12035-020-02060-8