Neuroprotective potential of a TrkB-FL-derived cell-penetrating peptide in cochlear synaptopathy and noise-induced hearing loss.

Abstract

Background: 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 (IHCs) and spiral ganglion neurons (SGNs). 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.

Methods: We employed an ex vivo model of excitotoxicity, where excitotoxicity was induced in cochlear explants by overstimulation of excitatory glutamate receptors, and an in vivo model of noise overexposure. The effects of excitotoxicity on the neurotrophic system and cell architecture were established by immunohistochemistry. Hearing function was evaluated in vivo by the auditory brainstem responses (ABR) test, performed before and after noise overexposure.

Results: In this study, we evaluated the therapeutic potential in the inner ear of MTFL₄₅₇, a cell-penetrating peptide designed to prevent TrkB-FL degradation in brain excitotoxicity. MTFL₄₅₇ showed efficient distribution across cochlear cell types in both ex vivo and in vivo models, supporting its ability to reach the inner ear and suggesting that it can cross the blood-labyrinth barrier after systemic administration. In explants undergoing excitotoxicity, MTFL₄₅₇ prevented TrkB-FL dysregulation, partially restored downstream prosurvival signaling, and significantly reduced neuronal damage and features associated with cochlear synaptopathy. In vivo, despite known sex-dependent differences in susceptibility to noise-induced damage, treatment with MTFL₄₅₇ preserved auditory function and synaptic integrity in both males and females, although the magnitude of protection varied between sexes. Together, these findings support a protective effect of MTFL₄₅₇ in models of excitotoxic cochlear injury.

Conclusions: These results support the therapeutic potential of peptide MTFL₄₅₇ for treatment of NIHL and possibly other types of sensorineural hearing loss likewise associated with excitotoxicity.