Farnesol mitigates methotrexate-induced intestinal toxicity by enhancing SIRT1, PPAR-γ, and Nrf2 signaling and attenuating Bax/cytochrome c/caspase-3-mediated apoptosis.

OBJECTIVES: The adherence to methotrexate (MTX) prolonged therapy in various cancers and autoimmune disorders is restricted due to its deleterious effects on several organs, like the liver, kidney, and intestine. Farnesol (FAR), a sesquiterpene alcohol found in various foods, essential oils, and herbs, exhibited promising antioxidant and anti-inflammatory impact in diverse experiments. The purpose of our study was to examine the possible mitigation of MTX-induced intestinal damage by FAR and the molecular pathways involved.

METHODS: The rats were orally administered FAR (10 mg/kg) for 10 days and a single i.p. injection of MTX (20 mg/kg) on day 5. On day 11, samples of duodenal tissue were obtained for biochemical, histological, and molecular assessments.

RESULTS: Our results demonstrated that FAR markedly ameliorated the degenerative changes induced by MTX in the duodenal mucosa along with preservation of mucosal goblet cells as manifested by PAS and Alcian blue staining. Besides, FAR enhanced the antioxidant and anti-inflammatory defenses via up-regulated expressions of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins. Moreover, the anti-inflammatory activity of FAR was emphasized by the substantial decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) duodenal contents in MTX-treated rats. Ultimately, FAR reduced duodenal apoptosis by down-regulating Bcl-2-associated X protein (Bax), cytochrome c, and cleaved caspase-3, while up-regulating B-cell lymphoma 2 (Bcl-2) expression demonstrated by the immunohistochemical investigation.Conclusion: FAR could protect against intestinal toxicity caused by MTX and thus increase the tolerability and adherence to prolonged MTX therapy.