The disruption and hyperpermeability of blood-labyrinth barrier mediates cisplatin-induced ototoxicity.

Abstract

The ototoxic mechanisms of cisplatin on the organ of Corti and spiral ganglion neurons have been extensively studied, while few studies have been focused on the stria vascularis (SV). Herein, we verified the functional and morphological impairment in SV induced by a single injection of cisplatin (12 mg/kg, I.P.), represented by a reduction in Endocochlear Potentials (EP) and strial atrophy, and explored underlying mechanisms. Our results revealed increased extravasation of chromatic tracers (Evans blue dye and FITC-dextran) around microvessels after cisplatin exposure. The increased vascular permeability could be attributed to changes of pericytes (PCs) and perivascular-resident macrophage-like melanocytes (PVM/Ms) in number or morphology, as well as the enhanced level of HIF-1α and downstream VEGF. This capillary leakage led to a high accumulation of cisplatin in the perivascular space in SV, and disrupted the integrity of blood-labyrinth barrier (BLB). Also, tight junction (ZO-1) loosening and Na+, K+-ATPase damage was considered to be other critical contributors of BLB breakdown, which resulted in EP drop and consequent hearing loss. This study explored the role of stria vascularis in cisplatin-induced ototoxicity in terms of BLB hyperpermeability and pointed to a novel therapeutic target for the prevention of cisplatin-related hearing loss.

• Authors: Jiayi Gu, Ling Tong, Xin Lin, Yuming Chen, Hao Wu, Xueling Wang, Dehong Yu
• Journal: Toxicology letters (Toxicol Lett) Vol. 354 Pg. 56-64 (Jan 01 2022) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 34757176 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (toxicity)
• Cisplatin (toxicity)
• Cochlea (blood supply, drug effects)
• Disease Models, Animal
• Male
• Mice
• Ototoxicity (etiology)
• Permeability (drug effects)
• Stria Vascularis (drug effects)