Pericytes of Stria Vascularis Are Targets of Cisplatin-Induced Ototoxicity: New Insights into the Molecular Mechanisms Involved in Blood-Labyrinth Barrier Breakdown

Abstract

The stria vascularis (SV) contributes to cochlear homeostasis and consists of three layers, one of which contains the blood-labyrinthic barrier (BLB), with a large number of bovine cochlear pericytes (BCPs). Cisplatin is a chemotherapeutic drug that can damage the SV and cause hearing loss. In this study, cell viability, proliferation rate, cytotoxicity and reactive oxygen species production were evaluated. The protein content of phospho-extracellular signal-regulated kinases (ERK) 1/2, total ERK 1/2, phospho-cytosolic phospholipase A2 (cPLA2), total cPLA2 and cyclooxygenase 2 (COX-2) and the release of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) from BCPs were analyzed. Finally, the protective effect of platelet-derived growth factor (PDGF-BB) on BCPs treated with cisplatin was investigated. Cisplatin reduced viability and proliferation, activated ERK 1/2, cPLA2 and COX-2 expression and increased PGE2 and VEGF release; these effects were reversed by Dexamethasone. The presence of PDGF-BB during the treatment with cisplatin significantly increased the proliferation rate. No studies on cell regeneration in ear tissue evaluated the effect of the PDGF/Dex combination. The aim of this study was to investigate the effects of cisplatin on cochlear pericytes and propose new otoprotective agents aimed at preventing the reduction of their vitality and thus maintaining the BLB structure.

Cisplatin ototoxicity mechanism and antagonistic intervention strategy: a scope review

“…Cisplatin could induce the damage of bovine cochlear pericytes (BCPs) that regulate BLB permeability, thereby disrupting cochlear homeostasis. Additional platelet-derived growth factor (PDGF-BB) induced recovery of BCP proliferation in the presence of cisplatin ( Anfuso et al, 2022 ). Mannitol intravenous injections at t = 6 h reduced cisplatin ototoxicity by increasing the permeability of the blood labyrinth barrier (BLB) without exacerbating cisplatin trafficking into cochlear cells at t = 0 h in rats.…”

N-Acetyl-L-cysteine Affects Ototoxicity Evoked by Amikacin and Furosemide Either Alone or in Combination in a Mouse Model of Hearing Threshold Decrease

“…Of note, aminoglycoside antibiotics produce hearing loss and vestibular dysfunction due to permanent hair cell loss [1,2], whereas loop diuretics usually cause hearing loss by acting on the stria vascularis, producing edema and a temporary loss of function, resulting in a decrease in endo-cochlear potential [3]. The molecular processes involved in hair cell survival, death and regeneration as a result of the action of ototoxic agents have been evaluated in various in vivo and in vitro studies [4][5][6][7][8][9].…”