Trigonelline promotes auditory function through nerve growth factor signaling on diabetic animal models

Abstract

Background: Protection of cochlear function and reconstruction of neuronal networks in damaged auditory sensory structures is crucial for therapeutic treatment of diabetic hearing loss. Nerve growth factor (NGF) has been used as a novel therapeutic target to protect against the neurodegenerative effects of Diabetes Mellitus (DM).

Purpose: We aimed to evaluate the potential effect of trigonelline (TRG) on reducing auditory damage produced by DM using NGF as a potential marker.

Method: Docking simulations were carried out using Autodock Vina software and visualized using Discovery Studio. Morphological analysis of hair cells and neuromasts was performed on alloxan-induced diabetic zebrafish by fluorescence and scanning electron microscopy. Blockage of NGF receptor phosphorylation with K-252a was used to evaluate TRG and NGF action. Further assessment of NGF by ELISA on a primary culture of spiral ganglion cells was performed as a marker of neuronal function on the hearing system. Finally, auditory function was assessed in LepR(^db/db) mice using auditory brainstem response (ABR) and transient evoked otoacoustic emission (TEOAE) during 8 weeks.

Results: Docking simulations showed that TRG binds to the active site of NGF through molecular interactions with Lysine88 (Lys88) and Tyrosine52 (Tyr52). TRG treatment significantly reduced hair cell loss and neuromast damage in diabetic zebrafish (P < .05). Further evaluation revealed a significant increase in the number of neuromasts after NGF administration (P < .001). TRG and NGF action was suppressed during blockage of NGF receptor phosphorylation. Moreover, spiral ganglion cells revealed significant elevation on NGF values after TRG treatment (P < .05). In vivo evaluation of LepR(^db/db) mice revealed a significant reduction in the auditory damage produced under diabetic progression, characterized by reduced ABR hearing threshold shifts and increased signal-to-noise ratio in TEOAE (P < .05).

Conclusions: This study suggests that the enhanced hearing function produced by TRG may be mediated by NGF, providing a potential therapeutic strategy for diabetic hearing loss.

Keywords: Auditory brainstem response (ABR); Hair cells; Molecular docking; Transient evoked otoacoustic emission (TEOAE); Zebrafish; db/db mice.