Fayez A.M.Zakaria S.Moustafa D.Department of Pharmacology and ToxicologyFaculty of PharmacyMSA UniversityOctober City 6GizaEgypt; Department of Pharmacology and ToxicologyFaculty of PharmacyOctober 6 UniversityOctober City 6GizaEgypt2020-01-092020-01-0920187533322https://doi.org/10.1016/j.biopha.2018.05.145PubMed ID 29879626https://t.ly/kNq39ScopusMSA Google ScholarHepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of ?-smooth muscle actin (?-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-?), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-? iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing ?-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties. � 2018 Elsevier Masson SASEnglishOctober University for Modern Sciences and Artsجامعة أكتوبر للعلوم الحديثة والآدابUniversity of Modern Sciences and ArtsMSA UniversityAntimicrobial sensitivityGastriccancer H.pyloriAlpha lipoic acidHepatic stellate cellsInflammatory responsesMethotrexateNrf2/HO-1 pathwayOxidative stress?-Smooth muscle actinalkaline phosphatasealpha smooth muscle actinaspartate aminotransferasecaspase 3cyclooxygenase 2glutathioneheme oxygenase 1hydroxyprolineinducible nitric oxide synthasemessenger RNAmethotrexatethioctic acidtranscription factor Nrf2tumor necrosis factorantioxidantbiological markerheme oxygenase 1methotrexatethioctic acidtranscription factor Nrf2alanine aminotransferase blood levelalkaline phosphatase blood levelanimal experimentanimal modelanimal tissueantiinflammatory activityantioxidant activityArticleaspartate aminotransferase blood levelcell activationcontrolled studydrug mechanismenzyme linked immunosorbent assayhepatic stellate cellhistopathologylipid peroxidationliver functionliver injuryliver protectionliver tissuemalemRNA expression levelnonhumanpriority journalprotein expression levelrattissue homogenateanimalapoptosischemistrydrug effecthepatic stellate cellinflammationlivermetabolismoxidative stresspathologypathophysiologysignal transductionAnimalsAntioxidantsApoptosisBiomarkersHeme Oxygenase-1Hepatic Stellate CellsInflammationLiverMaleMethotrexateNF-E2-Related Factor 2Oxidative StressRatsSignal TransductionThioctic AcidArticlehttps://doi.org/10.1016/j.biopha.2018.05.145PubMed ID 29879626