Expression Patterns Of Histone Deacetylases In Experimental Stroke And Potential Targets For Neuroprotection

[Objective] Ischemic stroke is one of the most common diseases in neurology, with a high morbidity and mortality rate and still in need of safe and effective treatment. Histone deacetylase (HDAC) inhibitors exert neuroprotective effects in both cellular and animal models of ischaemic stroke. However, which HDAC isoform (or isoforms) mediates this beneficial effect has not yet been determined. The main purpose of this research is to explore which selective HDAC inhibitors play a role in neural protection. This study is aimed to provide a theoretical basis for the treatment of ischemic stroke in clinic.[Methods] Mice middle cerebral artery occlusion (MCAO) models were established. Brain cortex was extracted at 3h,12h,24h and 48h after reperfusion. RT-PCR was utilized to analyse the mRNA expression of HDAC isotypes. We selected the isotypes with meaningful expression trend to further explore the protein expression level by western blotting. Oxygen and glucose deprivation (OGD) model were utilized on primary cortex neurons. RT-PCR and western blotting were applied to detect mRNA and protein expression of HDAC3 and 6 at 15min,3h, and 24h after reperfusion. Then, we detected the survival and late apoptosis rate of primary neurons with MTT and PI staining after inhibiting HDAC3 and 6 gene expression separately with shRNA.[results] HDACs (HDAC 1-11) were all expressed in normal and ischemic mice brains, with different expression levels. The mRNA levels of HDAC1,2 and 5 were decreased, while HDAC3,6 and 11 were increased after reperfusion, suggestting a potential value for further study. Western blotting showed the same trend of HDAC 1,2,5,6, and 11 in protein levels, and the results of immunofluorescence indicated that HDAC3 and 6 was mainly expressed in neurons in the cortex. After treatment with OGD, the expression of HDAC3 began to increase at 3h and reached the peak at 24h, while HDAC6 reached its summit at 3h and began to decrease at 24h. Moreover, inhibiting HDAC3 or 6 with shRNA increased the survival rate in OGD treated primary neurons.[Conclusion] HDAC isotypes showed different expression levels and trends after ischemic stroke, which suggested their different functions after ischemic stroke. Selectively inhibiting some isotypes may have neural protective effects. HDAC3 and 6 may play an important role after ischemic stroke. The selective inhibitors may have potential value in stu- dy of ischemic stroke.