title: Natural terpenes prevent mitochondrial dysfunction, oxidative stress and release of apoptotic proteins during nimesulide-hepatotoxicity in rats.
abstract: Nimesulide, an anti-inflammatory and analgesic drug, is reported to cause severe hepatotoxicity. In this study, molecular mechanisms involved in deranged oxidant-antioxidant homeostasis and mitochondrial dysfunction during nimesulide-induced hepatotoxicity and its attenuation by plant derived terpenes, camphene and geraniol has been explored in male Sprague-Dawley rats. Hepatotoxicity due to nimesulide (80 mg/kg BW) was evident from elevated SGPT, SGOT, bilirubin and histo-pathological changes. Antioxidants and key redox enzymes (iNOS, mtNOS, Cu/Zn-SOD, Mn-SOD, GPx and GR) were altered significantly as assessed by their mRNA expression, Immunoblot analysis and enzyme activities. Redox imbalance along with oxidative stress was evident from decreased NAD(P)H and GSH (56% and 74% respectively; P<0.001), increased superoxide and secondary ROS/RNS generation along with oxidative damage to cellular macromolecules. Nimesulide reduced mitochondrial activity, depolarized mitochondria and caused membrane permeability transition (MPT) followed by release of apoptotic proteins (AIF; apoptosis inducing factor, EndoG; endonuclease G, and Cyto c; cytochrome c). It also significantly activated caspase-9 and caspase-3 and increased oxidative DNA damage (level of 8-Oxoguanine glycosylase; P<0.05). A combination of camphene and geraniol (CG; 1:1), when pre-administered in rats (10 mg/kg BW), accorded protection against nimesulide hepatotoxicity in vivo, as evident from normalized serum biomarkers and histopathology. mRNA expression and activity of key antioxidant and redox enzymes along with oxidative stress were also normalized due to CG pre-treatment. Downstream effects like decreased mitochondrial swelling, inhibition in release of apoptotic proteins, prevention of mitochondrial depolarization along with reduction in oxidized NAD(P)H and increased mitochondrial electron flow further supported protective action of selected terpenes against nimesulide toxicity. Therefore CG, a combination of natural terpenes prevented nimesulide induced cellular damage and ensuing hepatotoxicity.
authors.affiliation: Herbal Research Section, CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, India.
authors.forename: Brijesh Kumar
authors.initials: BK
authors.lastname: Singh
authors.forename: Madhulika
authors.initials: M
authors.lastname: Tripathi
authors.forename: Bhushan P
authors.initials: BP
authors.lastname: Chaudhari
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Pandey
authors.forename: Poonam
authors.initials: P
authors.lastname: Kakkar
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001688:Biological Products / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004249:DNA Damage; D004579:Electron Transport / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009711:Nucleotides / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010539:Permeability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000633:toxicity*; D013729:Terpenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D001688:Biological Products; D009711:Nucleotides; D016877:Oxidants; D013449:Sulfonamides; D013729:Terpenes; D053148:Caspase 3; D053453:Caspase 9; C012655:nimesulide