Buspirone attenuated methotrexate‐induced hippocampal toxicity in rats by regulating Nrf2/HO‐1, PPAR‐γ, NF‐κB/nNOS, and ROS/NLRP3/caspase‐1 signaling pathways.

Methotrexate (MTX) is a chemotherapeutic agent widely used to treat a variety of tumors. Nonetheless, MTX‐induced hippocampal neurotoxicity is a well‐defined dose‐limiting adverse effect that limits clinical utility. Proinflammatory cytokine production and oxidative stress are possible mechanisms for MTX‐induced neurotoxicity. Buspirone (BSP), a partial agonist of the 5‐HT1a receptor (5‐HT1aR), has emerged as an anxiolytic drug. BSP has been shown to possess antioxidant and anti‐inflammatory effects. The current study investigated BSP's potential anti‐inflammatory and antioxidant effects in attenuating MTX‐induced hippocampal toxicity. Rats received either BSP (1.5 mg/kg) orally for 10 days and MTX (20 mg/kg) i.p. on Day 5. BSP administration markedly protected hippocampal neurons from drastic degenerated neuronal changes induced by MTX. BSP significantly attenuated oxidative injury by downregulating Kelch‐like ECH‐associated protein 1 expression while potently elevating hippocampal Nrf2, heme oxygenase‐1, and peroxisome proliferator‐activated receptor expression. BSP dampened inflammation by reducing NO2−, tumor necrosis factor‐alpha, IL‐6, and interleukin 1 beta levels mediated by downregulating NF‐κB and neuronal nitric oxides synthase expression. Moreover, BSP potently counteracted hippocampal pyroptosis by downregulating NLRP3, ASC, and cleaved‐caspase‐1 proteins. Therefore, BSP may represent a promising approach to attenuate neurotoxicity in patients receiving MTX. [ABSTRACT FROM AUTHOR]