Protective effects of histone deacetylase inhibition by Scriptaid on brain injury in neonatal rat models of cerebral ischemia and hypoxia

摘要

Background: Neonatal hypoxia-ischemia brain damage (HBID) can cause a series of neurological sequelae, such as movement and cognitive impairment, and there is currently no clinically effective treatment. Changes in epigenetic processes had been shown to be involved in the development of a series of neurodegenerative diseases, and HDAC inhibition by Scriptaid had been shown to reduce severe traumatic brain injury by suppressing inflammatory responses. This study investigated the protective effect of HDAC inhibition by Scriptaid after HBID. Methods: We established the neonatal rat HBID model, and used intraperitoneal injection of HDAC inhibitor scriptaid as a treatment. 7 days after HBID, nuclear magnetic resonance imaging (MRI) was used to detect infarct volume. The otarod test, wire hang test and Morris water maze were used to evaluate the HBID model of neurobehavioral dysfunction. Immunoblotting, immunofluorescence, and quantitative real-time PCR (RT-qPCR) were used to detect gene expression. Results: HDAC inhibition by Scriptaid treatment could not only reduce the infarct volume and neuronal degeneration in HBID rats, but also helped to improve their neurobehavioral dysfunction. 7 days after HBID, the expression of HDAC-1, HDAC-2 and HDAC-3 in the infarct volume of HBID + Veh group rats were much more than that in sham group (P<0.05), but Scriptaid could significantly inhibit those expression (P<0.05), and significantly increased the acetylation of H3 and H4 in HBID rats. In vivo and vitro results demonstrated that Scriptaid had no significant effect on oligodendrocyte MBP protein expression after OGD, but Scriptaid -treated microglia cultures had protective effects on OGD-treated OLG, M1 microglia suppressed OLG activity after OGD, and M2 enhanced its activity. In vivo experiments at 7 days after HBIDI injury showed that Scriptaid could promote the polarization of microglia into M2 microglia, reduced the expression of pro-inflammatory factors, and enhance the expression of anti-inflammatory cytokines. Conclusion: After HBID, HDAC inhibitor Scriptaid inhibits inflammatory responses and protects the brain by promoting the polarization of microglia in brain tissue to M2 microglia.