Calcium blockers protect against sensory epithelial damage and hearing loss in Cx26-cKO mice

Mutations in the GJB2 gene represent one of the most prevalent genetic causes of non-syndromic sensorineural hearing loss. Accumulating evidence suggests that degeneration of the cochlear sensory epithelium and developmental abnormalities in the organ of Corti constitute the primary pathological manifestations of GJB2-associated hereditary deafness. However, the precise mechanism of hair cell death caused by GJB2 mutation is still unclear. As key components of cochlear gap junction channels that mediate intercellular communication, connexin 26 (Cx26) facilitates the bidirectional transport of ions, ATP, glucose, and other metabolites between adjacent cells. Genetic ablation of Cx26 has been shown to disrupt ion circulation in cochlear hair cells. In this study, we observed a marked elevation of intracellular calcium levels in cochlear hair cells of Cx26-conditional knockout (Cx26-cKO) mice. Notably, sustained calcium overload is known to initiate multiple detrimental pathophysiological cascades. To investigate whether pharmacological modulation of calcium signalling could mitigate the auditory pathology, we constructed a Cx26-cKO mouse model, and treated with continuous intraperitoneal injection of the calcium blockers verapamil or nimodipine to evaluate their hearing and hair cell loss. The untreated Cx26-cKO mice showed high-frequency hearing loss accompanied by extensive outer hair cell loss in the basal turn of the cochlea. Strikingly, both verapamil- and nimodipine-treated groups demonstrated significant preservation of auditory function and hair cell survival. In summary, our results suggest that calcium blockers may be an important means of protecting hair cells from damage in Cx26-cKO mice, and this protective effect may even be extended to other inner ear disorders.