Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats
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Date
2018
Authors
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Elsevier Masson SAS
Series Info
Biomedicine and Pharmacotherapy
105
105
Scientific Journal Rankings
Abstract
Hepatic 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 SAS
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Keywords
October University for Modern Sciences and Arts, جامعة أكتوبر للعلوم الحديثة والآداب, University of Modern Sciences and Arts, MSA University, Antimicrobial sensitivity, Gastric, cancer H., pylori, Alpha lipoic acid, Hepatic stellate cells, Inflammatory responses, Methotrexate, Nrf2/HO-1 pathway, Oxidative stress, ?-Smooth muscle actin, alkaline phosphatase, alpha smooth muscle actin, aspartate aminotransferase, caspase 3, cyclooxygenase 2, glutathione, heme oxygenase 1, hydroxyproline, inducible nitric oxide synthase, messenger RNA, methotrexate, thioctic acid, transcription factor Nrf2, tumor necrosis factor, antioxidant, biological marker, heme oxygenase 1, methotrexate, thioctic acid, transcription factor Nrf2, alanine aminotransferase blood level, alkaline phosphatase blood level, animal experiment, animal model, animal tissue, antiinflammatory activity, antioxidant activity, Article, aspartate aminotransferase blood level, cell activation, controlled study, drug mechanism, enzyme linked immunosorbent assay, hepatic stellate cell, histopathology, lipid peroxidation, liver function, liver injury, liver protection, liver tissue, male, mRNA expression level, nonhuman, priority journal, protein expression level, rat, tissue homogenate, animal, apoptosis, chemistry, drug effect, hepatic stellate cell, inflammation, liver, metabolism, oxidative stress, pathology, pathophysiology, signal transduction, Animals, Antioxidants, Apoptosis, Biomarkers, Heme Oxygenase-1, Hepatic Stellate Cells, Inflammation, Liver, Male, Methotrexate, NF-E2-Related Factor 2, Oxidative Stress, Rats, Signal Transduction, Thioctic Acid