title: Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Sinn
authors.forename: Se-Jeong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kon
authors.initials: K
authors.lastname: Chu
authors.forename: Keun-Hwa
authors.initials: KH
authors.lastname: Jung
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: Lee
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Song
authors.forename: Jeong-Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Dong-Kyu
authors.initials: DK
authors.lastname: Park
authors.forename: Sang
authors.initials: S
authors.lastname: Kun Lee
authors.forename: Manho
authors.initials: M
authors.lastname: Kim
authors.forename: Jae-Kyu
authors.initials: JK
authors.lastname: Roh
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D014635:Valproic Acid; D006655:Histone Deacetylases