title: Hepatoprotective effect of withanolide-rich fraction in acetaminophen-intoxicated rat: decisive role of TNF-α, IL-1β, COX-II and iNOS.
abstract: BACKGROUND
  Overdose of acetaminophen (APAP) is common in humans and is often associated with hepatic damage. Withania somnifera (L.) Dunal (Solanaceae) shows multiple pharmacological activities including antioxidant and anti-inflammatory potential.
  
  
  OBJECTIVE
  To evaluate the possible mechanism of hepatoprotective activity of withanolide-rich fraction (WRF) isolated from a methanolic extract of Withania somnifera roots.
  
  
  METHODS
  Hepatotoxicity was induced by oral administration of APAP (750 mg/kg, p.o.) for 14 d. The control group received the vehicle. APAP-treated animals were given either silymarin (25 mg/kg) or graded doses of WRF (50, 100 and 200mg/kg) 2 h prior to APAP administration. Animals were killed on 15th day and blood and liver tissue samples were collected for the further analysis.
  
  
  RESULTS
  In WRF-treated group, there was significant and dose-dependent (p < 0.01 and p < 0.001) decrease in serum bilirubin, ALP, AST and ALT levels with significant and dose-dependent (p < 0.01 and p < 0.001) increase in hepatic SOD, GSH and total antioxidant capacity. The level of MDA and NO decreased significantly (p < 0.01) by WRF treatment. Up-regulated mRNA expression of TNF-α, IL-1β, COX-II and iNOS was significantly down-regulated (p < 0.001) by WRF. Histological alternations induced by APAP in liver were restored to near normality by WRF pretreatment.
  
  
  CONCLUSIONS
  WRF may exert its hepatoprotective action by alleviating inflammatory and oxido-nitrosative stress via inhibition of TNF-α, IL-1β, COX-II and iNOS.
authors.affiliation: a Center for Innovation in Nutrition, Health and Disease, Interactive Research School for Health Affairs , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Santosh T
authors.initials: ST
authors.lastname: Devkar
authors.affiliation: b Department of Pharmacology , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Kandhare
authors.affiliation: a Center for Innovation in Nutrition, Health and Disease, Interactive Research School for Health Affairs , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Anand A
authors.initials: AA
authors.lastname: Zanwar
authors.affiliation: c Interactive Research School in Health Affairs , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Suresh D
authors.initials: SD
authors.lastname: Jagtap
authors.affiliation: a Center for Innovation in Nutrition, Health and Disease, Interactive Research School for Health Affairs , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Surendra S
authors.initials: SS
authors.lastname: Katyare
authors.affiliation: b Department of Pharmacology , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Subhash L
authors.initials: SL
authors.lastname: Bodhankar
authors.affiliation: a Center for Innovation in Nutrition, Health and Disease, Interactive Research School for Health Affairs , Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: Mahabaleshwar V
authors.initials: MV
authors.lastname: Hegde
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics; D032341:Withania / Q000737:chemistry; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D008055:Lipids; D010936:Plant Extracts; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; D000082:Acetaminophen; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2
keywords: COX-II; cyclic voltammeter; inflammation; oxido-nitrosative stress; paracetamol-induced toxicity; withaferin A