Methotrexate (MTX) is an effective antineoplastic drug associated with wide organ toxicity. Accumulating evidence implicates oxidative stress to be a leading underlying mechanism of MTX‐induced neurotoxicity. The study explores antioxidant potential of virgin coconut oil (VCO) or Moringa oleifera seed oil (MOO) in MTX‐induced oxidative stress‐mediated cerebral neurotoxicity and inflammation in rats. Rats treated with VCO or MOO (5 ml/kg bw) for 17 days were administered MTX (20 mg/kg, intraperitoneally) on day 14 only. Cerebral activities of acetylcholinesterase, antioxidant enzymes, lipid peroxidation, reduced glutathione and nitric oxide levels as well as cytokines were evaluated. MTX‐induced neurotoxic alterations were significantly abrogated by MOO and VCO supplementation via inhibition of cholinesterase, oxidative stress, and anti‐inflammatory mechanisms. VCO and MOO showed comparable antioxidant potentials with the standards in DPPH and FRAP assays. VCO and MOO are promising natural oils for modulating MTX neurotoxicity in cancer patients. Practical applications Methotrexate chemotherapy induces neurotoxicity in cancer patients, and this is a source of worry for clinicians. This study reports, for the first time, the beneficial health effects of functional food oils, Moringa oleifera seed oil, and virgin coconut oil against anticancer drug methotrexate‐induced cerebral neurotoxicity. Supplementation of these natural oils may be beneficial in the prevention of cerebral neurotoxic side effect in cancer patients undergoing methotrexate chemotherapy.

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