Abstract
Background: During development, oligodendrocyte (OL) lineage cells are susceptible to injury, leading to life-long clinical neurodevelopmental decits, which lack effective treatments. Drugs targeting epigenetic modications that inhibit histone deacetylases (HDACs) protect from many clinical neurodegenerative disorders. Aim: This study aimed to investigate the therapeutic potential of histone deacetylase 2/3 (HDAC2/3) inhibitor MI192 on white matter (WM) pathology in a model of neonatal rat brain injury.Methods: Wistar rats (8.5-day-old, n = 32) were used to generate brain tissues. The tissues were cultured and then randomly divided into four groups and treated as following: group I (sham); the tissues were cultured under normoxia, group II (vehicle); DMSO only, group III (injury, INJ); the tissues were exposed to 20 minutes oxygen-glucose deprivation (OGD) insult, and group IV (INJ + MI192); the tissues were subjected to the OGD insult and then treated with the MI192 inhibitor. On culture day 10, the tissues were xed for biochemical and histological examinations. Results: The results showed that inhibition of HDAC2/3 activity alleviated WM pathology. Specically, MI192 treatment signicantly reduced cell death, minimized apoptosis, and mitigates the loss of the MBP+ OLs and their precursors (NG2+ OPCs). Additionally, MI192 decreased the density of reactive microglia (OX−42+). These ndings demonstrate that the inhibition of HDAC2/3 activity post-insult alleviates WM pathology through mechanism(s) including preserving OL lineage cells and suppressing microglial activation. Conclusion: The ndings of this study suggest that HDAC2/3 inhibition is a rational strategy to preserve WM or reverse its pathology upon newborn brain injury. Keywords: Brain injury, Epigenetics, MI192, Microglia, Oligodendrocyte