Manipulating the blood labyrinth barrier with mannitol to prevent cisplatin-induced hearing loss

Abstract

Cisplatin, a chemotherapeutic medication, remains in the cochlea indefinitely, causing permanent hearing loss. Mannitol, a diuretic medication, has been shown to increase the permeability of the blood labyrinth barrier (BLB). We hypothesize that mannitol increases the permeability of the BLB and therefore increases the rate of entry and egression of cisplatin and entry of otoprotective agents. Rats treated with cisplatin (t = 0) were given mannitol at either t = 0, t = 6 or t = 0,6 h. Another group of rats were treated with cisplatin with mannitol at 0 h and NAC/STS with and without mannitol at 6 h. Concurrent mannitol (t = 0) transiently increased cisplatin entry into the inner ear and exacerbated cisplatin-induced hearing loss. Delayed mannitol (t = 6) did not significantly increase cisplatin entry into the inner ear and preserved inner ear functionality and structure. Additional-delayed mannitol (t = 0,6) showed that the 2nd dose of mannitol prevented exacerbation of cisplatin with mannitol-induced hearing loss. A combination of delayed NAC/STS with mannitol (t = 6) was better than NAC/STS (t = 6) alone at providing partial to full protection against cisplatin with mannitol-induced hearing loss. In conclusion, mannitol injections at t = 6 h reduced cisplatin ototoxicity (instead of exacerbating cisplatin ototoxicity at t = 0 h), and it enhanced the otoprotective efficacy of antioxidants. This may provide an important therapeutic strategy to prevent cisplatin-induced hearing loss, a direct implication in protection against hearing loss in cisplatin chemotherapy.

Keywords: Antioxidant protection against cisplatin-induced hearing loss; Cisplatin ototoxicity; Cochlear pharmacokinetics of cisplatin; Manipulating the blood labyrinth barrier; Mannitol.