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

Abstract

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.

Gastrodin ameliorates neuroinflammation in Alzheimer’s disease mice by inhibiting NF-κB signaling activation via PPARγ stimulation

“…Cell experiments have found that PPARγ, as a potential drug target for treating neurodegenerative diseases, chiefly mediates the anti-inflammatory, anti-Aβ, anti-apoptotic and anti-oxidant effects [ 14 , 15 ]. In terms of anti-inflammation, PPARγ is expressed in both monocytes and macrophages, which, after activation, inhibits monocytes or macrophages from producing inflammatory mediators IL-1β, IL-6, TNF-α, as well as inducible nitric oxide synthase [ 16 ]. PPARγ inhibits the proinflammatory gene expressions at the transcriptional level by antagonizing the activities of transcription factors like NF-κB, AP-1 and STAT1 [ 17 ], and its agonists can effectively inhibit the inflammatory molecule production mediated by microglia and astrocytes in the central nervous system [ 18 , 19 ].…”