Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Zagazig, Sharkia Governorate, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia Governorate, Egypt.
Neurotox Res. 2020 Feb;37(2):380-396. doi: 10.1007/s12640-019-00095-x. Epub 2019 Aug 13.
Cisplatin is a widely used chemotherapeutic agent in treating various types of cancers. However, it can induce neurotoxicity and nephrotoxicity, limiting its dose and clinical use. Although previous studies indicated the direct link between cisplatin-induced central neurotoxicity and oxidative stress, the exact mechanism is not completely understood. Therefore, herein we investigated the effects of prophylactic and concurrent treatment with (-)-epigallocatechin-3-gallate (EGCG), a natural polyphenolic neuroprotective antioxidant, on cisplatin-induced brain toxicity in rats to delineate its molecular mechanism of action. We found that cisplatin initiated a cascade of genetic, biological, and histopathological changes in the brain cortex, inducing inflammatory cytokines, appearance of scattered inflammatory cells, nitro-oxidative stress, and apoptotic proteins in the cerebral cortex. However, EGCG not only protected against cisplatin-induced inflammatory burden but also ameliorated the induction of nitro-oxidative stress and apoptotic proteins triggered by cisplatin in the cerebral cortex of pre- and co-treated rats with respect to their unprotected counterparts. EGCG anti-inflammatory effect here may be attributed to the downregulation of nuclear factor kappa B (NF-κB). Additionally, this natural polyphenol significantly ameliorated cisplatin-elicited reduction in cerebral cortex brain-derived neurotrophic factor and acetylcholine esterase. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream heme oxygenase-1 (HO-1) by EGCG prophylactic and concurrent administration here seems also to play a key role in the protective impact of EGCG against cisplatin toxicity through enhancing total antioxidant capacity. Thus, EGCG can be used as a promising prophylactic adjuvant for preventing the development of brain inflammation and oxidative damage associated with cisplatin chemotherapy.
顺铂是一种广泛用于治疗各种类型癌症的化疗药物。然而，它会引起神经毒性和肾毒性，限制了其剂量和临床应用。尽管先前的研究表明顺铂诱导的中枢神经毒性与氧化应激之间存在直接联系，但确切的机制尚不完全清楚。因此，本研究旨在探讨预防性和同时性给予（-）-表没食子儿茶素没食子酸酯（EGCG），一种天然多酚神经保护抗氧化剂，对顺铂诱导的大鼠脑毒性的影响，以阐明其作用机制。我们发现，顺铂在大脑皮质中引发了一系列遗传、生物和组织病理学变化，诱导炎症细胞因子、散在炎症细胞的出现、硝基-氧化应激和大脑皮质中的凋亡蛋白。然而，EGCG 不仅能防止顺铂引起的炎症负担，还能改善顺铂对预治疗和同时治疗大鼠大脑皮质中硝基-氧化应激和凋亡蛋白的诱导，与未受保护的大鼠相比。EGCG 的抗炎作用可能归因于核因子 kappa B（NF-κB）的下调。此外，这种天然多酚显著改善了顺铂引起的大脑皮质脑源性神经营养因子和乙酰胆碱酯酶的减少。EGCG 预防性和同时性给药上调核因子红细胞 2 相关因子 2（Nrf2）及其下游血红素加氧酶-1（HO-1），通过增强总抗氧化能力，似乎也在 EGCG 对顺铂毒性的保护作用中发挥关键作用。因此，EGCG 可用作预防与顺铂化疗相关的脑炎症和氧化损伤的有前途的预防辅助剂。
