Protective effect of gallic acid against cisplatin-induced ototoxicity in rats

Abstract Introduction: Cisplatin is an antineoplastic agent widely used in the treatment of a variety of cancers. Ototoxicity is one of the main side-effects restricting the use of cisplatin. Objective: The purpose of this study was to investigate the protective efficacy of gallic acid, in biochemical, functional and histopathological terms, against ototoxicity induced by cisplatin. Methods: Twenty-eight female Sprague Dawley rats were included. Rats were randomly assigned into four groups of seven animals each. Cisplatin group received a single intraperitoneal dose of 15 mg/kg cisplatin. Gallic acid group received intraperitoneal gallic acid at 100 mg/kg for five consecutive days. Cisplatin + gallic acid group received intraperitoneal gallic acid at 100 mg/kg for five consecutive days and a single intraperitoneal dose of 15 mg/kg cisplatin at 3rd day. A control group received 1 mL intraperitoneal saline solution for five consecutive days. Prior to drug administration, all rats were exposed to the distortion product otoacoustic emissions test. The test was repeated on the 6th day of the study. All rats were then sacrificed; the cochleas were removed and set aside for biochemical and histopathological analyses. Results: In cisplatin group, Day 6 signal noise ratio values were significantly lower than those of the other groups. Also, malondialdehyde levels in cochlear tissues were significantly higher, superoxide dismutase and glutathione peroxidase activities were significantly lower compared to the control group. Histopathologic evaluation revealed erosion in the stria vascularis, degeneration and edema in the connective tissue layer in endothelial cells, impairment of outer hair cells and a decrease in the number of these calls. In the cisplatin + gallic acid group, this biochemical, histopathological and functional changes were reversed. Conclusion: In the light of our findings, we think that gallic acid may have played a protective role against cisplatin-induced ototoxicity in rats, as indicated by the distortion product otoacoustic emissions test results, biochemical findings and immunohistochemical analyses.

【摘要】引言：顺铂（Cisplatin）是广泛应用于多种恶性肿瘤治疗的抗肿瘤药物。耳毒性（Ototoxicity）是制约其临床应用的主要不良反应之一。
研究目的：本研究旨在从生化、功能及组织病理学层面，探讨没食子酸（Gallic Acid）对顺铂诱导耳毒性的保护作用。
方法：纳入28只雌性斯普拉格-道利（Sprague Dawley）大鼠，随机分为4组，每组7只。顺铂组：单次腹腔注射15 mg/kg顺铂；没食子酸组：连续5天腹腔注射100 mg/kg没食子酸；顺铂+没食子酸组：连续5天腹腔注射100 mg/kg没食子酸，并于第3天单次腹腔注射15 mg/kg顺铂；对照组：连续5天腹腔注射1 mL生理盐水。给药前所有大鼠均接受畸变产物耳声发射（distortion product otoacoustic emissions）检测，于实验第6天重复该检测。随后处死所有大鼠，取出耳蜗用于生化及组织病理学分析。
结果：顺铂组实验第6天的信噪比（signal noise ratio）显著低于其余各组；与对照组相比，其耳蜗组织丙二醛（malondialdehyde）水平显著升高，超氧化物歧化酶（superoxide dismutase）及谷胱甘肽过氧化物酶（glutathione peroxidase）活性显著降低。组织病理学评估显示：血管纹（stria vascularis）出现糜烂，内皮细胞结缔组织层发生变性与水肿，外毛细胞（outer hair cells）受损且数量减少。在顺铂+没食子酸组，上述生化、组织病理学及功能学改变均得到有效逆转。
结论：结合本研究的畸变产物耳声发射检测结果、生化指标及免疫组织化学分析结果，我们认为没食子酸对大鼠顺铂诱导的耳毒性具有明确的保护作用。