Transtympanic Injection of Antioxidant-Eluting Microparticles for Otoprotection From Cisplatin Toxicity in a Mouse Model

Introduction: Cisplatin is an effective chemotherapeutic with risks of ototoxicity, and transtympanic injections of antioxidant formulations may provide local otoprotection. We tested a novel antioxidant-eluting microparticle for its otoprotection potential against systemic cisplatin using cochlear electrophysiology and labyrinthine mitochondrial gene expression.

Methods: In total, 18 mice were assigned to 3 groups. All mice underwent baseline click-evoked auditory brainstem response (ABR) audiometry and right ear microparticle (MP) injections before beginning 42-day intraperitoneal (IP) administration regimens of either saline (Group 1, control) or cisplatin (Groups 2 and 3). These regimens consisted of 3x 4-day cycles of IP saline or cisplatin separated by 10 rest days. Group 1 (IP saline) received transtympanic empty MP (EMP), Group 2 (IP cisplatin) received transtympanic EMP, and Group 3 (IP cisplatin) received transtympanic N-acetylcysteine-MP (NAC-MP). On day 43, all mice underwent post-treatment ABR testing and vestibular epithelia harvest. Thresholds were analyzed with a mixed effects model and Tukey’s post-hoc tests, and were compared across pre and posttreatments, treatment groups, and injected and non-injected ears. Tissue was pooled by ear (left and right) and treatment group. RNA was extracted and analyzed via qRT-PCR for selected mitochondrial gene expression. Expression levels, relative to the non-injected untreated control, were compared (one way ANOVAs).

Results: We found that right ear thresholds in Group 3 (IP cisplatin, transtympanic NAC-MP) were similar to the left ears from Group 1 (IP saline, transtympanic EMP; p = 0.2761), and were lower than their paired non-injected left ears (p = 0.0375). Group 2 posttreatment thresholds were greater than Group 1 (p < 0.0001). Mitochondrial gene expression was similar across all treatment groups.

Conclusions: Transtympanic NAC MP injections provided functional otoprotection in cisplatin-exposed mice. The alterations in ABR thresholds were not accompanied by alterations in the expression of selected mitochondrial genes explored.