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 |
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| Authors: | Hanan S Althagafy Zeina W Sharawi Ashwaq H Batawi Hailah M Almohaimeed Wafa S Al-Thubiani Emad H M Hassanein Amal Rateb |
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| Institution: | 1. Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia;2. Department Biological Science, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia;3. Department of Basic Science, College of Medicine, Princess Nourah Bint Abdul Rahman University, Riyadh, Saudi Arabia;4. Department of Biology, Faculty of Applied Sciences, Umm Al-Qura University, Mecca, Saudi Arabia;5. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt;6. Department of Human Anatomy and Embryology, Faculty of Medicine, Assuit University, Assiut, Egypt
Department of Basic Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arbia |
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| 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. |
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| Keywords: | buspirone methotrexate NF-κB/nNOS Nrf2/HO-1 PPAR-γ ROS/NLRP3/caspase-1 |
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