Vinpocetine Mitigates Methotrexate-Induced Liver Injury in Rats Through Modulating Intercellular Communication

Abstract

Methotrexate (MTX) has been widely implemented in managing several malignancies, inflammatory conditions such as rheumatic arthritis, and autoimmune illnesses. Hepatotoxicity is a significant side effect of MTX, characterized by increased oxidative stress (OS) and inflammation. Vinpocetine (Vinpo) is a prescription medication with a favorable safety profile. It exerts anti-inflammatory and oxidant implications that might be novel candidates for protecting against MTX-induced hepatotoxicity. This study investigates the therapeutic impact of Vinpo against MTX-stimulated liver damage via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Rats are allocated into three groups: (1) the Control (saline); (2) the MTX-control (20 mg/kg; injected once i.p.), and (3) the Vinpo + MTX groups. Vinpo was administered orally for 7 days, during which MTX was given intraperitoneally once at the end of Day 3. The liver functions, OS markers, inflammatory mediators, Nrf2, HO-1, NF-κB, and apoptotic signals were estimated. Vinpo lead to enhancement in superoxide dismutase (SOD) enzyme activity, elevation in glutathione (GSH), and a hindrance in malondialdehyde (MDA). It also enhances Nrf2 and HO-1, inhibiting NF-κB (p65) expression and apoptotic markers. Moreover, Vinpo therapy, in conjunction with MTX, restores the normal histological structure of hepatic tissues. Our data suggested that Vinpo exerts a preventive effect against MTX-induced toxicity through anti-oxidative, anti-inflammatory, and apoptotic activities, mediated via Nrf2/HO-1/Nf-κB and caspase-3/Bax/Bcl-2 pathways.