title: Valproate ameliorates thioacetamide-induced fibrosis by hepatic stellate cell inactivation.
abstract: Valproic acid (VPA) has been reported as inhibitor of histone deacetylases (HDACs). Several reports indicated that HDACs play a crucial role in the pathogenesis of fibrosis and hepatic stellate cell (HSC) activation. The present study was aimed to evaluate the anti-fibrotic effect of VPA against thioacetamide (TAA)-induced hepatic fibrosis and activation of the HSC in rat. VPA and TAA were administrated intraperitoneally at the dose of 400 and 200 mg/kg each at 2 days interval, respectively for a period of 6 weeks. Administration of TAA significantly increased the absolute and relative liver weight, aspartate aminotransferase and alanine aminotransferase levels, which were significantly decreased by VPA treatment as compared to TAA control. VPA treatment prevents the TAA-induced activation of HSC and decreases collagen deposition and infiltration of inflammatory cells as revealed by Sirius red and H&E staining. Interestingly, VPA co-treatment led to significantly increase the DNA damage and apoptosis in the activated HSC as compared to TAA control. Further, TAA decreased the expression of matrix metalloproteinase-2 (MMP-2), while VPA co-treatment significantly increased the expression of MMP-2 as compared to respective control. The present study clearly demonstrated that VPA treatment significantly alleviates TAA-induced activation of HSC and subsequent hepatic fibrosis.
authors.affiliation: Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India These two authors contributed equally.
authors.forename: J S
authors.initials: JS
authors.lastname: Aher
authors.affiliation: Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India These two authors contributed equally.
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India.
authors.forename: S
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India.
authors.forename: K
authors.initials: K
authors.lastname: Tikoo
authors.affiliation: Department of Pharmacology and Toxicology, Facility for Risk Assessment and Intervention Studies, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab, India gbjena@gmail.com.
authors.forename: G
authors.initials: G
authors.lastname: Jena
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009929:Organ Size / Q000187:drug effects; D017208:Rats, Wistar; D013853:Thioacetamide; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D017392:Thiobarbituric Acid Reactive Substances; D013853:Thioacetamide; D014635:Valproic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D005978:Glutathione
keywords: HDAC inhibitor; Hepatic stellate cell; hepatic fibrosis; thioacetamide; valproic acid