Clonidine mitigates noise-induced hearing loss by regulating TRPC6-mediated calcium influx in cochlear hair cells.

Noise-induced hearing loss (NIHL) is a common auditory disorder driven by calcium overload, oxidative stress, and apoptosis in cochlear sensory hair cells. The transient receptor potential canonical 6 (TRPC6), a nonselective cation channel that can be activated by norepinephrine, is implicated in calcium influx and associated cellular damage. This study explores the protective effects of clonidine, an FDA-approved α2-adrenergic receptor agonist that reduces sympathetic nervous system activity and norepinephrine release, on NIHL in mice. Clonidine treatment significantly preserved hearing thresholds, reduced damage to outer hair cells and ribbon synapses, and suppressed TRPC6 channel activation induced by noise exposure. Mechanistically, clonidine alleviated calcium influx, inhibited the calcium-dependent MLCK-MRLC signaling pathway, and attenuated oxidative stress and apoptosis in cochlear hair cells. Molecular docking analyses demonstrated strong binding between norepinephrine and TRPC6, elucidating the regulatory role of clonidine in calcium signaling. These findings highlight clonidine's potential to prevent NIHL by maintaining intracellular calcium homeostasis and reducing cochlear damage via the modulation of norepinephrine and TRPC6 activity. TRPC6 emerges as a promising therapeutic target for preventing and managing noise-induced auditory dysfunction.