Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation

Neurobiology of Disease

Eun-Cheol Song¹  Sang Kun Lee²  Jae-Kyu Roh³  Soon-Tae Lee³  Dong-Kyu Park³  Se-Jeong Kim³  Keun-Hwa Jung⁴  Kon Chu⁴  Jeong-Min Kim⁴  Manho Kim⁴  Dong-In Sinn⁴ 

[1] Comprehensive Epilepsy Center, Seoul National University Hospital, Seoul, South Korea;Division of Epidemic Intelligence, Department of Disease Investigation and Surveillance, Korea Center for Disease Control and Prevention, Seoul, South Korea;Program in Neuroscience, Seoul National University, Seoul, South Korea;Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Stem Cell Research Center, Department of Neurology, Seoul National University Hospital, Neuroscience Research Institute of SNUMRC, Seoul, South Korea;

关键词: Intracerebral hemorrhage;    Histone deacetylase;    Valproic acid;    Apoptosis;    Inflammation;    ERK;   

DOI  :  

来源: DOAJ

【 摘 要 】

The modification of histone N-terminal tails by acetylation or deacetylation can alter the interaction between histones and DNA, and thus regulate gene expression. Recent experiments have demonstrated that valproic acid (VPA), a well-known anti-epileptic drug, can directly inhibit histone deacetylase (HDAC) activity and cause the hyperacetylation of histones. Moreover, VPA has been shown to mediate neuronal protection by activating signal transduction pathways and by inhibiting proapoptotic factors. In this study, we attempted to determine whether VPA alleviates cerebral inflammation and perihematomal cell death after intracerebral hemorrhage (ICH). Adult male rats received intraperitoneal injections of 300 mg/kg VPA or PBS twice a day after ICH induction. VPA treatment inhibited hematoma expansion, perihematomal cell death, caspase activities, and inflammatory cell infiltration. In addition, VPA treatment had the following expressional effects; it activated the translations of acetylated histone H3, pERK, pAKT, pCREB, and HSP70; up-regulated bcl-2 and bcl-xl but down-regulated bax; and down-regulated the mRNAs of Fas-L, IL-6, MMP-9, MIP-1, MCP-1, and tPA. VPA-treated rats also showed better functional recovery from 1 day to 4 weeks after ICH. Here we show that VPA induces neuroprotection in a murine ICH model and that its neuroprotective effects are mediated by transcriptional activation following HDAC inhibition.

【 授权许可】

Unknown