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 vestibular
apparatus. Gentamicin is known to cause irreversible bilateral ototoxicity. Autophagy induction has
been proposed as a target for prevention of gentamicin ototoxicity. Aim of the work: to investigate the
possible protective effect of autophagy induction by verapamil compared to rapamycin. Methods: This
experiment was conducted on 32 male guinea pigs. At the beginning each animal’s hearing status was
assessed using auditory brainstem response (ABR) audiometry. Then, they were divided into 4 equal
groups: Group 1: control group, Group 2: untreated gentamicin-induced ototoxicity group. Group 3:
gentamicin-induced ototoxicity treated concomitantly with rapamycin. Group 4: gentamicin-induced
ototoxicity treated concomitantly with verapamil. At the end of the experiment, ABR was repeated
then the animals were sacrificed, and blood samples were obtained for assaying of reduced glutathione
and malondialdehyde levels. The left cochlea was processed for scanning electron microscope, while
the 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 suggested
as a potential therapeutic approach to decrease gentamicin ototoxicity.