Protective Role of Epigallocatechin Gallate in a Rat Model of Cisplatin-Induced Cerebral Inflammation and Oxidative Damage: Impact of Modulating NF-κB and Nrf2
Protective Role of Epigallocatechin Gallate in a Rat Model of Cisplatin-Induced Cerebral Inflammation and Oxidative Damage: Impact of Modulating NF-κB and Nrf2
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DOI：
10.1007/s12640-019-00095-x
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发表时间：
2020-02-01
影响因子：
3.7
通讯作者：
Atteia, Hebatallah Husseini
中科院分区：
文献类型：
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作者：
Arafa, Manar Hamed;Atteia, Hebatallah Husseini
顺铂是广泛用于治疗各种类型癌症的化学治疗剂。但其可引起神经毒性和肾毒性，限制了其剂量和临床应用。虽然以前的研究表明顺铂诱导的中枢神经毒性和氧化应激之间的直接联系，但确切的机制并不完全清楚。因此，在此，我们研究了预防性和同时治疗（-）-表没食子儿茶素-3-没食子酸酯（EGCG），天然多酚类神经保护性抗氧化剂，顺铂诱导的大鼠脑毒性的影响，以描绘其分子作用机制。我们发现，顺铂引发了一系列的遗传，生物学和组织病理学变化的大脑皮层，诱导炎症细胞因子，外观分散的炎症细胞，硝基氧化应激和凋亡蛋白的大脑皮层。然而，表没食子儿茶素没食子酸酯不仅保护对顺铂诱导的炎症负荷，但也改善了诱导的硝基氧化应激和凋亡蛋白引发的顺铂在大脑皮层中的预处理和共同处理的大鼠相对于他们的未受保护的同行。EGCG的抗炎作用可能与下调核因子-κ B（NF-κ B）有关。此外，这种天然多酚显着改善顺铂引起的大脑皮层脑源性神经营养因子和乙酰胆碱酯酶的减少。通过EGCG预防性和同时给药，核因子红细胞2相关因子2（Nrf 2）及其下游血红素加氧酶-1（HO-1）的上调似乎也通过增强总抗氧化能力在EGCG对顺铂毒性的保护作用中发挥关键作用。因此，表没食子儿茶素没食子酸酯可用作预防性佐剂，用于预防与顺铂化疗相关的脑炎症和氧化损伤的发展。
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-kappa B). 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.