Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Eur J Pharmacol. 2019 Aug 15;857:172422. doi: 10.1016/j.ejphar.2019.172422. Epub 2019 May 30.
Cisplatin-induced acute renal injury is the most common and serious side effect, sometimes requiring discontinuation of the treatment. Thus, the development of new protective strategies is essential. The present study aimed to investigate the potential nephroprotective effect of tetramethylpyrazine (TMP) against acute renal damage induced by cisplatin in rats. Rats were administered 50 and 100 mg/kg TMP intraperitoneally before cisplatin (7 mg/kg). Acute nephrotoxicity was evident in cisplatin-treated rats where relative kidney weight, BUN and serum creatinine were markedly elevated. Cisplatin administration resulted in enhanced oxidative stress, evidenced by depleted GSH level as well as catalase and superoxide dismutase activities. Also, lipid peroxidation was boosted in comparison to the control. This was associated with inhibition of Nrf2 defense pathway. Moreover, cisplatin increased the expression of pro-inflammatory mediators in the kidney tissues. Cisplatin-induced apoptosis was depicted by elevated Bax mRNA expression and caspase-3 activity, as well as decreased Bcl2 mRNA expression. In addition, high mobility group box 1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway was significantly upregulated, while peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression was significantly diminished in cisplatin-treated rats. Cisplatin-induced nephrotoxicity, oxidative stress, inflammation, apoptosis and the effect on Nrf2 defense pathway and HMGB1/TLR4/NF-κB as well as PPAR-γ expression were markedly ameliorated by TMP administration. Given the major nephrotoxicity of cisplatin cancer chemotherapy, TMP might be a potential candidate for neoadjuvant chemotherapy due to its antioxidant, anti-inflammatory and anti-apoptotic effects, in addition to its effect on Nrf2, HMGB1/TLR4/NF-κB signaling pathway and PPAR-γ expression.
顺铂诱导的急性肾损伤是最常见和最严重的副作用，有时需要停止治疗。因此，开发新的保护策略至关重要。本研究旨在探讨川芎嗪（TMP）对顺铂诱导的大鼠急性肾损伤的潜在肾保护作用。大鼠腹腔注射 50 和 100mg/kg TMP 后，给予顺铂（7mg/kg）。顺铂处理的大鼠表现出明显的急性肾毒性，相对肾重、BUN 和血清肌酐明显升高。顺铂给药导致氧化应激增强，表现为 GSH 水平降低以及过氧化氢酶和超氧化物歧化酶活性降低。与对照组相比，脂质过氧化也增加了。这与 Nrf2 防御途径的抑制有关。此外，顺铂增加了肾脏组织中促炎介质的表达。顺铂诱导的细胞凋亡表现为 Bax mRNA 表达和 caspase-3 活性升高，Bcl2 mRNA 表达降低。此外，高迁移率族蛋白 1/ toll 样受体 4/核因子-κB（HMGB1/TLR4/NF-κB）信号通路显著上调，而过氧化物酶体增殖物激活受体-γ（PPAR-γ）表达在顺铂处理的大鼠中显著降低。TMP 给药显著改善了顺铂诱导的肾毒性、氧化应激、炎症、细胞凋亡以及对 Nrf2 防御途径和 HMGB1/TLR4/NF-κB 以及 PPAR-γ 表达的影响。鉴于顺铂癌症化疗的主要肾毒性，TMP 可能因其抗氧化、抗炎和抗凋亡作用，以及对 Nrf2、HMGB1/TLR4/NF-κB 信号通路和 PPAR-γ 表达的影响，成为新辅助化疗的潜在候选药物。
