{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:32:15Z","timestamp":1781069535540,"version":"3.54.1"},"reference-count":82,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST103-2314-B-037-044-MY2"],"award-info":[{"award-number":["MOST103-2314-B-037-044-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011645","name":"Kaohsiung Medical University Hospital","doi-asserted-by":"publisher","award":["KMUH 103-3R17"],"award-info":[{"award-number":["KMUH 103-3R17"]}],"id":[{"id":"10.13039\/501100011645","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg\/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1\/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg\/kg (p &lt; 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and\/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.<\/jats:p>","DOI":"10.3390\/ijms22115975","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T15:58:44Z","timestamp":1622563124000},"page":"5975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats"],"prefix":"10.3390","volume":"22","author":[{"given":"Chieh-Hsin","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Cheng","family":"Tsai","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Hsin","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keng-Liang","family":"Kuo","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Feng","family":"Su","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hui","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Lung","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S1474-4422(03)00266-7","article-title":"Stroke epidemiology: A review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century","volume":"2","author":"Feigin","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/brain\/124.2.249","article-title":"Subarachnoid haemorrhage: Diagnosis, causes and management","volume":"124","author":"Rinkel","year":"2001","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1161\/CIR.0000000000000485","article-title":"Heart disease and stroke statistics-2017 update: A report from the american heart association","volume":"135","author":"Benjamin","year":"2017","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/S0140-6736(07)60153-6","article-title":"Subarachnoid haemorrhage","volume":"369","author":"Kerr","year":"2007","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1161\/01.STR.25.7.1342","article-title":"Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage","volume":"25","author":"Broderick","year":"1994","journal-title":"Stroke"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/jcbfm.2012.57","article-title":"Pharmacologic reduction of angiographic vasospasm in experimental subarachnoid hemorrhage: Systematic review and meta-analysis","volume":"32","author":"Zoerle","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1161\/01.STR.16.4.562","article-title":"Cerebral vasospasm following aneurysmal subarachnoid hemorrhage","volume":"16","author":"Kassell","year":"1985","journal-title":"Stroke"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0163-7258(94)00080-M","article-title":"Mechanisms of cerebral vasospasm in subarachnoid haemorrhage","volume":"66","author":"Cook","year":"1995","journal-title":"Pharmacol. Ther."},{"key":"ref_9","first-page":"e519","article-title":"Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage","volume":"41","author":"Macdonald","year":"2010","journal-title":"Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1161\/hs0102.101080","article-title":"Predictors of cognitive dysfunction after subarachnoid hemorrhage","volume":"33","author":"Kreiter","year":"2002","journal-title":"Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"660","DOI":"10.3171\/jns.1951.8.6.0660","article-title":"Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms","volume":"8","author":"Ecker","year":"1951","journal-title":"J. Neurosurg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1161\/STROKEAHA.110.597914","article-title":"Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects","volume":"42","author":"Vergouwen","year":"2011","journal-title":"Stroke"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s00234-009-0575-y","article-title":"Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage","volume":"51","author":"Dankbaar","year":"2009","journal-title":"Neuroradiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1161\/01.STR.0000249008.18669.5a","article-title":"17beta-estradiol inhibits subarachnoid hemorrhage-induced inducible nitric oxide synthase gene expression by interfering with the nuclear factor kappa b transactivation","volume":"37","author":"Shih","year":"2006","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/01.STR.29.1.181","article-title":"Apoptosis of medial smooth muscle cells in the development of saccular cerebral aneurysms in rats","volume":"29","author":"Kondo","year":"1998","journal-title":"Stroke"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/01616412.1998.11740494","article-title":"Evidence for apoptosis in human intracranial aneurysms","volume":"20","author":"Hara","year":"1998","journal-title":"Neurol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/j.1750-3639.2002.tb00447.x","article-title":"Neuronal apoptosis in the dentate gyrus in humans with subarachnoid hemorrhage and cerebral hypoxia","volume":"12","author":"Nau","year":"2002","journal-title":"Brain Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1038\/sj.jcbfm.9600283","article-title":"Mechanisms of early brain injury after subarachnoid hemorrhage","volume":"26","author":"Cahill","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1097\/00004647-200404000-00007","article-title":"Caspase inhibitors prevent endothelial apoptosis and cerebral vasospasm in dog model of experimental subarachnoid hemorrhage","volume":"24","author":"Zhou","year":"2004","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1056\/NEJM199701023360106","article-title":"Intracranial aneurysms","volume":"336","author":"Schievink","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic acid defines a novel class of hdac inhibitors inducing differentiation of transformed cells","volume":"20","author":"Gottlicher","year":"2001","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"479364","DOI":"10.1155\/2010\/479364","article-title":"Molecular and therapeutic potential and toxicity of valproic acid","volume":"2010","author":"Chateauvieux","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1080\/j.1440-1614.2006.01815.x","article-title":"Anticonvulsants in bipolar disorder","volume":"40","author":"Bowden","year":"2006","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1007\/s00018-007-7079-x","article-title":"The mechanisms of action of valproate in neuropsychiatric disorders: Can we see the forest for the trees?","volume":"64","author":"Rosenberg","year":"2007","journal-title":"Cell Mol. Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/1874467210902010095","article-title":"Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection","volume":"2","author":"Monti","year":"2009","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2014.01.051","article-title":"Neuroprotective and anti-apoptotic effects of valproic acid on adult rat cerebral cortex through erk and akt signaling pathway at acute phase of traumatic brain injury","volume":"1555","author":"Zhang","year":"2014","journal-title":"Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1111\/j.1471-4159.2004.02406.x","article-title":"Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: Potential roles of histone deacetylase inhibition and heat shock protein induction","volume":"89","author":"Ren","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1124\/jpet.107.120188","article-title":"Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: Multiple mechanisms of action","volume":"321","author":"Kim","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.tins.2009.06.002","article-title":"Multiple roles of hdac inhibition in neurodegenerative conditions","volume":"32","author":"Chuang","year":"2009","journal-title":"Trends Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.neulet.2013.02.026","article-title":"Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for erk-mapk signaling","volume":"541","author":"Kautu","year":"2013","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1161\/01.STR.16.4.591","article-title":"Subarachnoid hemorrhage: Epidemiology, diagnosis, management, and outcome","volume":"16","author":"Bonita","year":"1985","journal-title":"Stroke"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/hipo.450050103","article-title":"Dentate gyrus destruction and spatial learning impairment after corticosteroid removal in young and middle-aged rats","volume":"5","author":"Conrad","year":"1995","journal-title":"Hippocampus"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1172\/JCI5357","article-title":"Heme oxygenase-1 gene induction as an intrinsic regulation against delayed cerebral vasospasm in rats","volume":"104","author":"Suzuki","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0165-0270(02)00344-8","article-title":"A murine model of subarachnoid hemorrhage-induced cerebral vasospasm","volume":"123","author":"Lin","year":"2003","journal-title":"J. Neurosci. Methods"},{"key":"ref_35","first-page":"e4157","article-title":"A low mortality rat model to assess delayed cerebral vasospasm after experimental subarachnoid hemorrhage","volume":"71","author":"Dudhani","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"H2551","DOI":"10.1152\/ajpheart.00616.2002","article-title":"Comparison of three rat models of cerebral vasospasm","volume":"283","author":"Gules","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12950-015-0074-3","article-title":"Valproic acid attenuates intercellular adhesion molecule-1 and e-selectin through a chemokine ligand 5 dependent mechanism and subarachnoid hemorrhage induced vasospasm in a rat model","volume":"12","author":"Chang","year":"2015","journal-title":"J. Inflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1161\/01.STR.27.3.504","article-title":"Subarachnoid injections of lysed blood induce the hsp70 stress gene and produce DNA fragmentation in focal areas of the rat brain","volume":"27","author":"Matz","year":"1996","journal-title":"Stroke"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/sj.jcbfm.9600069","article-title":"Role of p53 and apoptosis in cerebral vasospasm after experimental subarachnoid hemorrhage","volume":"25","author":"Zhou","year":"2005","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.3171\/jns.2005.102.6.1046","article-title":"Delayed cell death related to acute cerebral blood flow changes following subarachnoid hemorrhage in the rat brain","volume":"102","author":"Prunell","year":"2005","journal-title":"J. Neurosurg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1161\/01.STR.0000226995.27230.96","article-title":"Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage","volume":"37","author":"Cahill","year":"2006","journal-title":"Stroke"},{"key":"ref_42","first-page":"529","article-title":"Early brain injury following aneurysmal subarachnoid hemorrhage: Emphasis on cellular apoptosis","volume":"22","author":"Yuksel","year":"2012","journal-title":"Turk. Neurosurg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1054\/jocn.2002.1088","article-title":"Therapeutic effect of caspase inhibitors in the prevention of apoptosis and reversal of chronic cerebral vasospasm","volume":"9","author":"Aoki","year":"2002","journal-title":"J. Clin. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cheng, G., Wei, L., Zhi-Dan, S., Shi-Guang, Z., and Xiang-Zhen, L. (2009). Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway. BMC Neurosci., 10.","DOI":"10.1186\/1471-2202-10-7"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1097-2765(02)00482-3","article-title":"Mechanisms of caspase activation and inhibition during apoptosis","volume":"9","author":"Shi","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7415","DOI":"10.1523\/JNEUROSCI.17-19-07415.1997","article-title":"Activation of cpp32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury","volume":"17","author":"Yakovlev","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1146\/annurev.neuro.20.1.245","article-title":"Bcl-2 gene family in the nervous system","volume":"20","author":"Merry","year":"1997","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1161\/01.STR.0000229888.55078.72","article-title":"Akt\/gsk3beta survival signaling is involved in acute brain injury after subarachnoid hemorrhage in rats","volume":"37","author":"Endo","year":"2006","journal-title":"Stroke"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.3171\/jns.2000.93.6.1041","article-title":"Effects of mitogen-activated protein kinase inhibitors on cerebral vasospasm in a double-hemorrhage model in dogs","volume":"93","author":"Tibbs","year":"2000","journal-title":"J. Neurosurg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"207616","DOI":"10.1155\/2014\/207616","article-title":"Progesterone attenuates experimental subarachnoid hemorrhage-induced vasospasm by upregulation of endothelial nitric oxide synthase via akt signaling pathway","volume":"2014","author":"Chang","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/21224","article-title":"Activation of nitric oxide synthase in endothelial cells by akt-dependent phosphorylation","volume":"399","author":"Dimmeler","year":"1999","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1097\/00004647-200112000-00009","article-title":"Evidence of phosphorylation of akt and neuronal survival after transient focal cerebral ischemia in mice","volume":"21","author":"Noshita","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1038\/sj.jcbfm.9600303","article-title":"Activation of the akt\/gsk3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats","volume":"26","author":"Endo","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/02699050500284218","article-title":"The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions","volume":"24","author":"Yoon","year":"2006","journal-title":"Growth Factors"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1089\/neu.2015.4290","article-title":"Norepinephrine protects cerebral autoregulation and reduces hippocampal necrosis after traumatic brain injury via blockade of erk mapk and il-6 in juvenile pigs","volume":"33","author":"Armstead","year":"2016","journal-title":"J. Neurotrauma"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1089\/neu.2013.2962","article-title":"Tpa-S481A prevents impairment of cerebrovascular autoregulation by endogenous tpa after traumatic brain injury by upregulating p38 mapk and inhibiting et-1","volume":"30","author":"Armstead","year":"2013","journal-title":"J. Neurotrauma"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1042\/bj3030701","article-title":"Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation","volume":"303","author":"Stambolic","year":"1994","journal-title":"Biochem. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1089\/neu.2004.21.1168","article-title":"Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury","volume":"21","author":"Clausen","year":"2004","journal-title":"J. Neurotrauma"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1016\/S0028-3908(02)00215-0","article-title":"Regulation of akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium","volume":"43","author":"Li","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1161\/STROKEAHA.116.014738","article-title":"Valproate reduces delayed brain injury in a rat model of subarachnoid hemorrhage","volume":"48","author":"Hamming","year":"2017","journal-title":"Stroke"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.brainres.2017.12.018","article-title":"Acute in vivo effect of valproic acid on the GABAergic system in rat brain: A [11 C]Ro15-4513 microPET study","volume":"1680","author":"Bertelsen","year":"2018","journal-title":"Brain Res."},{"key":"ref_62","first-page":"81","article-title":"Valproic Acid Treatment after Experimental Subarachnoid Hemorrhage","volume":"120","author":"Tso","year":"2014","journal-title":"Funct. Rehabil. Neurosurg. Neurotraumatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.molbiopara.2009.06.001","article-title":"Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni","volume":"168","author":"Dubois","year":"2009","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"10014","DOI":"10.1073\/pnas.180316197","article-title":"Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation","volume":"97","author":"Richon","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","first-page":"2123","article-title":"Levels of histone H3 acetylation in peripheral blood mononuclear cells of acute cerebral infarction patients","volume":"94","author":"Shen","year":"2014","journal-title":"Zhonghua Yi Xue Za Zhi"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8641","DOI":"10.1038\/s41598-017-08535-4","article-title":"HDAC3 inhibition ameliorates spinal cord injury by immunomodulation","volume":"7","author":"Kuboyama","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ejphar.2016.12.026","article-title":"Isoliquiritigenin inhibits TNF-\u03b1-induced release of high-mobility group box 1 through activation of HDAC in human intestinal epithelial HT-29 cells","volume":"796","author":"Chi","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/sj.cdd.4401759","article-title":"Valproic acid induces extracellular signal-regulated kinase 1\/2 activation and inhibits apoptosis in endothelial cells","volume":"13","author":"Michaelis","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_69","first-page":"37","article-title":"Valproic acid, a molecular lead to multiple regulatory pathways","volume":"53","author":"Kostrouch","year":"2007","journal-title":"Folia Biol."},{"key":"ref_70","first-page":"886","article-title":"Different mechanisms of protection against apoptosis by valproate and Li+","volume":"266","author":"Mora","year":"1999","journal-title":"JBIC J. Biol. Inorg. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ijdevneu.2014.07.004","article-title":"Valproic acid attenuates the sup-pression of acetyl histone h3 and creb activity in an inducible cell model of machado-joseph disease","volume":"38","author":"Lin","year":"2014","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1293\/tox.26.29","article-title":"Change Trends of Organ Weight Background Data in Sprague Dawley Rats at Different Ages","volume":"26","author":"Piao","year":"2013","journal-title":"J. Toxicol. Pathol."},{"key":"ref_74","first-page":"624","article-title":"The Laboratory Rat: Relating Its Age with Human\u2019s","volume":"4","author":"Sengupta","year":"2013","journal-title":"Int. J. Prev. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"436","DOI":"10.3171\/jns.2007.106.3.436","article-title":"Attenuation of experimental subarachnoid hemorrhage\u2013induced cerebral vasospasm by the adenosine A2A receptor agonist CGS 21680","volume":"106","author":"Lin","year":"2007","journal-title":"J. Neurosurg."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1179\/016164101101199144","article-title":"Improved rat model for cerebral vasospasm studies","volume":"23","author":"Meguro","year":"2001","journal-title":"Neurol. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"457","DOI":"10.3171\/2008.6.17622","article-title":"Attenuation of cerebral vasospasm and secondary injury by 17beta-estradiol following experimental subarachnoid hemor-rhage","volume":"110","author":"Lin","year":"2009","journal-title":"J. Neurosurg."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s00701-006-0793-6","article-title":"The effect of an adenosine A1 receptor agonist in the treatment of experimental subarachnoid hemorrhage-induced cerebrovasospasm","volume":"148","author":"Lin","year":"2006","journal-title":"Acta Neurochir."},{"key":"ref_79","first-page":"374","article-title":"The effect of hydrogen sulphide on experimental cerebral vasospasm","volume":"27","author":"Emmez","year":"2017","journal-title":"Turk. Neurosurg."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"108117","DOI":"10.1016\/j.abb.2019.108117","article-title":"Carbon monoxide attenuates vasospasm and improves neurobehavioral function after subarachnoid hemorrhage","volume":"676","author":"Kamat","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1479-5876-10-80","article-title":"Trehalose treatment suppresses inflammation, oxidative stress, and vasospasm induced by experimental subarachnoid hemorrhage","volume":"10","author":"Echigo","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/2047-783X-18-21","article-title":"Induction of autophagy by cystatin C: A potential mechanism for prevention of cerebral vasospasm after experimental subarachnoid hemorrhage","volume":"18","author":"Liu","year":"2013","journal-title":"Eur. J. Med Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5975\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:45Z","timestamp":1760162985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":82,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115975"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115975","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,1]]}}}