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

Cited 131 time in Web of Science Cited 145 time in Scopus
Authors
Sinn, D. I.; Kim, S. J.; Chu, K.; Jung, K. H.; Lee, S. T.; Song, E. C.; Kim, J. M.; Park, D. K.; Kun Lee, S.; Kim, M.; Roh, J. K.
Issue Date
2007-04-03
Publisher
Elsevier
Citation
Neurobiol Dis. 2007 May;26(2):464-72. Epub 2007 Feb 23.
Keywords
AnimalsApoptosis Regulatory Proteins/drug effects/genetics/metabolismCell Death/drug effects/physiologyCerebral Hemorrhage/*drug therapy/metabolism/physiopathologyChemotaxis, Leukocyte/drug effects/physiologyDisease Models, AnimalEncephalitis/*drug therapy/metabolism/physiopathologyEnzyme Inhibitors/pharmacology/therapeutic useHistone Deacetylases/*antagonists & inhibitors/metabolismMaleNerve Degeneration/drug therapy/physiopathology/prevention & controlNeuroprotective Agents/*pharmacology/therapeutic useRNA, Messenger/drug effects/metabolismRatsRats, Sprague-DawleyRecovery of Function/drug effects/physiologySignal Transduction/drug effects/physiologyTranscriptional Activation/*drug effects/geneticsTreatment OutcomeValproic Acid/*pharmacology/therapeutic use
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.
ISSN
0969-9961 (Print)
Language
English
URI
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WNK-4N43RN8-3&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=152d3af4ccd9aad256173ee1e1b9114d

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17398106

http://hdl.handle.net/10371/22224
DOI
https://doi.org/10.1016/j.nbd.2007.02.006
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College of Medicine/School of Medicine (의과대학/대학원)Neuroscience (뇌신경과학전공)Journal Papers (저널논문_뇌신경과학전공)
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