Abstract
According to the World Health Organization, there are 1.3 billion people around the world living with some degree of noise-induced hearing loss (NIHL) and 1 billion young adults at risk of developing NIHL. Currently, there are no FDA-approved drugs that protect the inner ear against NIHL. To address this need, my thesis aims to investigate the therapeutic potential of quinoxaline derivatives for NIHL. There is a large library of FDA-approved, commercially available quinoxaline-based drugs, and a study in zebrafish by Zallocchi, et al. (2021) found that quinoxaline derivatives were protective against excitotoxicity-induced hearing loss. The derivatives that conferred the most protection in zebrafish were selected for use in my thesis. The present study tested five derivatives – Qx3, Qx17, Qx23, Qx34, and Qx62 – in an in vivo mouse model for synaptopathy. Their therapeutic effects were quantified using auditory brainstem responses (ABR), distortion product otoacoustic emissions (DPOAE), and morphological analysis. The derivatives’ bioavailability was assessed using an in silico ADME assay from SwissADME. A kinome activity assay was performed on organs of Corti to assess changes in kinase activity following noise exposure. We found that Qx34 and Qx62 had the most beneficial effects on noise-exposed animals; they recovered ABR and DPOAE thresholds the fastest, preserved ABR wave I amplitude and latency, and prevented pre-synaptic ribbon loss. According to SwissADME, all five derivatives are highly orally bioavailable and will passively cross the blood-brain barrier, which means they will likely cross the blood-labyrinth barrier. The kinome assay predicted the upregulation of DDR1 and Tec kinases up to 21d post-noise exposure. This is a novel finding as these kinases have not been previously linked to NIHL pathogenesis. In all, Qx34 and Qx62 are the top derivatives from this study, and future studies are needed to assess their otoprotection following oral administration and at a higher noise level.