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조회428

박민정Min Jung Park

충남대학교

J. Adv. Res., Nov 27 2023, S2090-1232(23)00358-2 | https://doi.org/10.1016/j.jare.2023.11.020 CORM‑2 Reduces Cisplatin Accumulation in the Mouse Inner Ear and Protects against Cisplatin-induced Ototoxicity

Ah-Ra Lyu^a, Soo Jeong Kim ^a, Min Jung Park ^a,c, Yong-Ho Park ^a,b

^aBrain Research Institute, College of Medicine, Chungnam National University, Daejeon 35015, Korea

^bDepartment of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea

^cLead contact

Corresponding authors : Min Jung Park, Yong-Ho Park

Abstract

Cisplatin is a life-saving anticancer compound used to treat multiple solid malignant tumors, while it causes permanent hearing loss. There is no known cure, and the FDA has not approved any preventative treatment for cisplatin-based ototoxicity. This study investigated whether the carbon monoxide (CO)-releasing tricarbonyldichlororuthenium (II) dimer, CORM-2, reverses cisplatin-induced hearing impairment and reduces cisplatin accumulation in the mouse inner ear. Male 6-week-old BALB/c mice were randomly assigned to one of the following groups: control (saline-treated, i.p.), CORM-2 only (30 mg/kg, i.p., four doses), cisplatin only (20 mg/kg, i.p., one dose), and CORM-2 + cisplatin, to determine whether cisplatin-based hearing impairment was alleviated by CORM-2 treatment. Our results revealed CORM-2 significantly attenuated cisplatin-induced hearing loss in young adult mice. CORM-2 co-treatment significantly decreased platinum accumulation in the inner ear and activated the plasma membrane repair system of the stria vascularis. Moreover, CORM-2 co-treatment significantly decreased cisplatin-induced inflammation, apoptosis, and cochlear necroptosis. Because the stria vascularis is the likely cochlear entry point of cisplatin, we next focused on the microvasculature. Cisplatin induced increased extravasation of a chromatic tracer (fluorescein isothiocyanate [FITC]-dextran, MW 75 kDa) around the cochlear microvessels at 4 days post-treatment; this extravasation was completely inhibited by CORM-2 co-therapy. CORM-2 co-treatment effectively maintained the integrity of stria vascularis components including endothelial cells, pericytes, and perivascular-resident macrophage-type melanocytes. CORM-2 co-therapy substantially protects against cisplatin-induced ototoxicity by reducing platinum accumulation and toxic cellular stress responses. These data indicate that CORM-2 co-treatment may be translated into clinical strategy to reduce cisplatin-induced hearing loss.

논문정보

형식Research article
게재일2023년 11월 (BRIC 등록일 2023-12-01)
연구진국내 연구진
분야 의약학 > 응용의학

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