Glabridin Plays Dual Action to Augment the Efficacy and Attenuate the Hepatotoxicity of Methotrexate in Arthritic Rats

[Image: see text] Glabridin is chemically an isoflavane class of natural phenols and is found mainly in the roots of Glycyrrhiza glabra. It has several beneficial pharmacological actions for the management of inflammatory disorders as well as can counteract drug-induced toxic effects. On the other hand, methotrexate (MTX) is the first-line disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis. However, its treatment is associated with major side effects like hepatotoxicity. In the quest to explore a suitable combination therapy that can improve the efficacy and reduce the hepatotoxicity of MTX, we hypothesized that glabridin might serve the purpose for which there is no literature precedent to date. We explored the antiarthritic efficacy of MTX in the presence or the absence of glabridin using Mycobacterium-induced arthritic model in rats. The results of reduction in paw swelling, inhibition of serum cytokines (TNF-α, IL-6, and IL-1β), and improvement in the bone joints from radiological and histopathological findings suggest that glabridin can substantially augment the antiarthritic efficacy of MTX. Further, results of concomitant glabridin treatment with MTX in the experimental time frame demonstrate that glabridin could considerably prevent the MTX-induced hepatic alteration in serum biochemical markers (SGPT and SGOT) and oxidative stress markers (malondialdehyde (MDA) and glutathione reduced (GSH)). Moreover, glabridin showed a marked effect in impeding the regulation of NF-κB/IκBα and Nrf2/Keap1 pathways in the hepatic tissues. The results of simultaneous administration of glabridin with MTX in the rat model indicate that glabridin had no pronounced effect of causing severe alteration in the pharmacokinetic behavior of MTX. In summary, glabridin can significantly potentiate the antiarthritic efficacy of MTX and can also minimize its hepatotoxicity via the inhibition of inflammation and oxidative stress. Further research should be performed to develop glabridin as a phytotherapeutics for the improved efficacy and better tolerability of MTX at the reduced dose level of MTX.