Restoring autophagy flux by rolipram attenuates ototoxicity in Hearing loss.

Sensorineural hair cell loss is one of the major contributors to hearing loss. Failure of autophagy flux has been reported as a major factor that impairs hearing sense during various ototoxic conditions. In this study we investigated whether enhancing autophagy can mitigate kanamycin and furosemide induced cytotoxicity by using rolipram to restore the autophagy flux. Upon dose dependent treatment of kanamycin and furosemide, we observed depletion in the viability and impaired autophagy flux. Treatment with the PDE4 inhibitor rolipram restored autophagy activity and significantly improved cell survival. Consistent with an autophagy dependent mechanism, the protective effect of rolipram was abolished by chloroquine or Atg7 knockdown, confirming that intact autophagy flux is required for cellular protection. In vivo, rolipram attenuated kanamycin and furosemide induced hearing loss and preserved cochlear hair cells. Notably, ribbon synapses of inner hair cells were also maintained, indicating that autophagy enhancement protected both cellular integrity and synaptic function. These findings demonstrate that restoring autophagy flux represents a viable therapeutic strategy against ototoxic injury, and identify rolipram as a potential pharmacological agent for protecting auditory cells and hearing function.