Ethanolic Extract of Capparis decidua Fruit Ameliorates Methotrexate-Induced Hepatotoxicity by Activating Nrf2/HO-1 and PPARγ Mediated Pathways

Introduction: Methotrexate, a folate antimetabolite, immunosuppressant and cytotoxic chemotherapeutic agents employed for malignant conditions. Continuous exposure of methotrexate produces adverse side effects especially liver toxicity. Recently, medicinal plants are gaining an importance owing to their phytoconstituents which are responsible for their medicinal value. Capparis decidua is one such medicinal plant widely used in the traditional system of medicine. No study has focused the mechanism of hepatoprotective property of Capparis decidua via Nrf2/HO-1 and PPAR gamma signaling pathway. Hence the study was mainly focused on its ability to modulate Nrf2 and PPAR gamma signaling in the methotrexate induced hepatotoxicity in Wistar rats. Materials and Methods: 30 female Wistar albino rats were divided into five groups. Following a single dose of methotrexate (20 mg/kg, intraperitoneally) injection, Wistar rats were orally administered with Capparis decidua at a doses of 250 mg/kg and 500mg/kg for 14 days. AST, ALT and ALP, antioxidants like GST, GPx, GR, were assessed in hepatic tissue. LPO, H2O2, OH radicals were assessed. mRNA expression of Nrf2, HO-1, PPAR gamma was carried using real-time PCR in hepatic tissue. Nrf2, TNF-alpha, IL-1 beta proteins were assessed using western blot. Results: Methotrexate administration significantly increased liver function marker, caused lipid peroxidation and decreased antioxidants levels. Treatment with Capparis decidua caused significant decrease in AST, ALT, ALP, levels and significant increase in GST, GPx, GR. Methotrexate decreased mRNA expression of Nrf2, HO-1, PPAR gamma. Capparis decidua prevented methotrexate induced liver injury by upregulating Nrf2 and PPAR gamma signaling pathway. Capparis decidua also suppressed inflammatory markers like TNF-alpha and IL-1 beta proteins. Conclusion: Capparis decidua has thus attenuated methotrexate induced hepatotoxicity and this could be via up-regulation of Nrf2/HO-1 and PPAR gamma pathways.