Targeting Autophagy Induction as A possible Protective Mechanism by Verapamil Compared to Rapamycin (Sirolimus) Against Gentamicin -Induced Ototoxicity in Guinea Pigs

Abstract

Background: Ototoxicity is a harmful feature of the cochlea or auditory nerve and sometimes vestibularapparatus. Gentamicin is known to cause irreversible bilateral ototoxicity. Autophagy induction hasbeen proposed as a target for prevention of gentamicin ototoxicity. Aim of the work: to investigate thepossible protective effect of autophagy induction by verapamil compared to rapamycin. Methods: Thisexperiment was conducted on 32 male guinea pigs. At the beginning each animal’s hearing status wasassessed using auditory brainstem response (ABR) audiometry. Then, they were divided into 4 equalgroups: Group 1: control group, Group 2: untreated gentamicin-induced ototoxicity group. Group 3:gentamicin-induced ototoxicity treated concomitantly with rapamycin. Group 4: gentamicin-inducedototoxicity treated concomitantly with verapamil. At the end of the experiment, ABR was repeatedthen the animals were sacrificed, and blood samples were obtained for assaying of reduced glutathioneand malondialdehyde levels. The left cochlea was processed for scanning electron microscope, whilethe right cochlea was processed for histopathology and LC3-II immunohistochemistry. Results:Verapamil revealed superiority compared to rapamycin proved by significant improvement in ABR,histopathological results, in addition to its antioxidant effect. Conclusion: verapamil could be suggestedas a potential therapeutic approach to decrease gentamicin ototoxicity.