Mohamed A. Al-Griw(1), Mansur E. Shmela(2), Mohamed M. Elhensheri(3) and Emad M. Bennour(4*)
1- Department of Histology and Genetics, Faculty of Medicine, University of Tripoli, Tripoli, Libya
2- Department of Preventive Medicine, Genetics & Animal Breeding, Faculty of Veterinary Medicine, University of Tripoli, Tripoli, Libya
3- Rostock University Medical Centre, Rostock, Germany
4- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tripoli, Tripoli, Libya
Background: During development, oligodendrocyte (OL) lineage cells are susceptible to injury, leading to life-long clinical neurodevelopmental deficits, which lack effective treatments. Drugs targeting epigenetic modifications 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 4 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 fixed for biochemical and histological examinations.
Results: The results showed that inhibition of HDAC2/3 activity alleviated WM pathology. Specifically, MI192 treatment significantly 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 findings 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 findings 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, Oligodendrocytes.