Neuroprotection against cochlear synaptopathy and noise-induced hearing loss by a TrkB-FL-derived cell-penetrating peptide

[EN] Noise-induced hearing loss (NIHL) is the second leading cause of deafness globally. However, effective pharmacological treatments remain unavailable. Excitotoxicity, an early NIHL event, is a central mechanism in degeneration of cochlear synapses established between inner hair cells and spiral ganglion neurons. This excitotoxic damage can trigger the degradation of the neurotrophic TrkB receptor, thereby inhibiting brain-derived neurotrophic factor (BDNF) signaling and challenging neurotrophin-based therapies for hearing loss. Here, we evaluate the therapeutic potential in the inner ear of MTFL457, a cell-penetrating peptide that prevents TrkB-FL degradation during brain excitotoxicity. This peptide efficiently distributes through cochlear cells in both ex vivo (explants) and in vivo (noise-overexposed) models. In explants undergoing excitotoxicity, MTFL457 prevents TrkB-FL dysregulation, recovers downstream prosurvival signaling, and reduces neurodegeneration and cochlear synaptopathy. Furthermore, despite sexual dimorphism in noise damage susceptibility in vivo, MTFL457 preserves hearing function and synapses, demonstrating its therapeutic potential for NIHL and possibly other types of sensorineural hearing loss likewise associated with excitotoxicity.