The Rescue Effect And Mechanism Of Histone Deacetylase Inhibitor On Parkinson Disease

Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the reduced dopamine content and selectively progressive loss of dopaminergic neurons in substantial nigra of midbrain.Oxidative stress is one of the most important mechanisms in the pathogenesis of PD. The study found that substantia nigra of PD patients was always in a state of high oxygen stress.Epigenetic histone acetylation and deacetylation play vital roles in the Parkinson’s disease and other neurodegenerative diseases, histone deacetylase inhibitors have protective effect on neurodegenerative disease.MT2is an oxidative stress resistance factor and histone deacetylase inhibitors can increase MT2expression. The dopamine transporter (dopamine transporter, DAT) and vesicular transporter (vesicular monoamine transporter, VMAT2) play a very important role in the maintenance of the central nervous system of dopamine monoamine substance balance. CpG island methylation of VMAT2and DAT promoter region has great variation, from2%to90%, which showed that epigenetic regulation was an important mechanism of VMAT2and DAT expression. Therefore,whether the protective effect of histone deacetylase inhibitors on PD and whether the changes of MT2、DAT VMAT2expression is mediated by epigenetic mechanisms to achieve? These need to be further studied.Objective To investigate the protective effect of histone deacetylase inhibitor on Parkinson’s disease and its possible mechanisms.Methods Groups in the experiment.The control group was treated with vehicle(DMSO)> the model group was treated with rotenone (0.5μM/L,24h) or MPP+(1mM/L,24h), the sodium butyrate group was pretreated with sodium butyrate (1mM/L、2mM/L、5mM/L,48h) before rotenone or MPP+was added. 1. The four methylthiazolyl tetrazolium (MTT) assay was used to detect cell viability, Release of LDH, DCFH-DA fluorescent probe was used to check the level of reactive oxygen species, flow cytometry was used to determine hypodiploid peak and apoptotic rates.2. The mRNA expression of MT2was detected by Real Time PCR.3. The bisulfite sequencing PCR was used to detected the methylation status of MT2、DAT and VMAT2promotor region.4. The H3ac level of MT2、DAT and VMAT2promotor region was detected by Chromatinn immunoprecipitation assay.Results1. The effect of HDACI on dopaminergic neural cell lines damage induced by rotenone and MPP+.(1) Rotenone and MPP+could reduce cell viability of dopaminergic neural cell lines.(2) HDACI significantly decreased the apoptotic rate induced by rotenone and MPP+(3) HDACI significantly reduced the level of reactive oxygen species induced by rotenone and MPP+2. Real Time PCR results showed that sodium butyrate could increase the expression of MT2mRNA.3. HDACI could decrease promoter region methylation rate of MT2、DAT、VMAT2gene.4. HDACI group could increase H3ac levels of MT2、DAT、VMAT2gene promoter region.Conclusions The HDACI (sodium butyrate)confered significant protection against Parkinson’s disease, and this effect might mediate epigenetic mechanism of upregulation expression of MT2and monoamine transporter to achieve.