Dietary zinc protects against methotrexate-induced neurotoxicity in rats via modulation of oxidative stress, inflammation and neuronal energy metabolism

Abstract

Background: Increasing incidence of cancers and cancer chemotherapy-induced neurotoxicities makes it imperative to research compounds with neuroprotective potential that can do not impede therapy. Objective: To examine the effect of dietary zinc supplementation on methotrexate-induced changes in neurobehaviour and neurochemistry and hippocampal morphology in rats. Methods: Adult male rats were assigned into five groups of twelve animals each. Group were normal control and methotrexate control fed standard rodent chow and three groups of rats fed zinc supplemented diet at 25, 50 and 100 mg/kg of feed respectively. Standard and zinc supplemented diet were administered daily for 21 days. Animals in the normal control were administered intraperitoneal injection (i.p) of normal saline at 2ml/kg, while those in the methotrexate and zinc groups were administered i.p methotrexate at 20 mg/kg/day on days 19-21. On day 22, animals were exposed to behavioural paradigm (open field, Y-maze, radial arm maze, elevated plus maze and behavioural despair test). After the last behavioural test, animals were sacrificed and blood taken for the assessment of Tumour necrosis factor-α, interleukin 1β and interleukin 10), malondialdehyde levels and total antioxidant capacity. The hippocampus was either homogenised for the assessment of dopamine, serotonin, acetylcholine and brain derived neurotropic factor levels or processed for histological study. Results: Dietary zinc protected against methotrexate-induced changes in weight, food intake, cognition, hippocampal histomorphology and neuron specific enolase immunohistochemistry. Conclusion: Dietary zinc supplementation protects against methotrexate induced neurotoxicities by modulating oxidative stress, inflammatory markers brain neurotransmitters and metabolism in rats.