Notoginsenoside R1 Attenuates Cisplatin-Induced Ototoxicity by Inducing Heme Oxygenase-1 Expression and Suppressing Oxidative Stress

被引:0
|
作者
Lin, Yi-Chun [1 ]
Ho, Yi-Jung [2 ,3 ]
Lin, Yuan-Yung [1 ]
Liao, Ai-Ho [4 ]
Kuo, Chao-Yin [1 ]
Chen, Hang-Kang [1 ]
Chen, Hsin-Chien [1 ]
Wang, Chih-Hung [1 ,5 ]
Shih, Cheng-Ping [1 ]
机构
[1] Triserv Gen Hosp, Natl Def Med Ctr, Dept Otolaryngol Head & Neck Surg, Taipei 11490, Taiwan
[2] Natl Def Med Ctr, Sch Pharm, Taipei 11490, Taiwan
[3] Natl Def Med Ctr, Grad Inst Life Sci, Taipei 11490, Taiwan
[4] Natl Taiwan Univ Sci & Technol, Grad Inst Biomed Engn, Taipei 10607, Taiwan
[5] Taipei City Hosp, Dept Ophthalmol, Taipei, 103212, Taiwan
关键词
cisplatin; cochlea; hair cells; notoginsenoside; ototoxicity; oxidative stress; PANAX-NOTOGINSENG; INDUCED NEPHROTOXICITY; SODIUM THIOSULFATE; CELLS; PREVENTION; PROTECTS; PATHWAY;
D O I
10.3390/ijms252111444
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Cisplatin-induced ototoxicity occurs in approximately half of patients treated with cisplatin, and pediatric patients are more likely to be affected than adults. The oxidative stress elicited by cisplatin is a key contributor to the pathogenesis of ototoxicity. Notoginsenoside R1 (NGR1), the main bioactive compound of Panax notoginseng saponins, has antioxidant and antiapoptotic effects. This study investigated the ability of NGR1 to protect against cisplatin-induced damage in auditory HEI-OC1 cells and neonatal murine cochlear explants. The viability of HEI-OC1 cells treated with NGR1 and cisplatin was greater than that of cells treated with cisplatin alone. The results of Western blots and immunostaining for cleaved caspase-3 revealed that the level of cleaved caspase-3 in the cells treated with cisplatin was repressed by NGR1. NGR1 attenuated cisplatin-induced cytotoxicity in HEI-OC1 cells. Intracellular reactive oxygen species (ROS) were detected with a DCFDA assay and immunostaining for 4-HNE. The result revealed that its expression was induced by cisplatin and was significantly reduced by NGR1. Moreover, NGR1 can promote heme oxygenase-1 (HO-1) expression at both the mRNA and protein levels. ZNPPIX, an HO-1 inhibitor, was administered to cisplatin-treated cells to investigate the role of HO-1 in the protective effect of NGR1. The suppression of HO-1 activity by ZNPPIX markedly abolished the protective effect of NGR1 on cisplatin-treated cells. Therefore, NGR1 protects cells from cisplatin-induced damage by activating HO-1 and its antioxidative activity. In cochlear explants, NGR1 protects cochlear hair cells and attenuates cisplatin-induced ototoxicity by inhibiting ROS generation. In the group treated with cisplatin alone, prominent loss of outer hair cells and severe damage to the structure of the stereociliary bundles of inner and outer hair cells were observed. Compared with the group treated with cisplatin alone, less loss of outer hair cells (p = 0.009) and better preservation of the stereociliary bundles of hair cells were observed in the group treated with cisplatin and NGR1. In conclusion, these findings indicate that NGR1 can protect against cisplatin-induced ototoxicity by inducing HO-1 expression and suppressing oxidative stress.
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页数:13
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