Quinolyl nitrone derivative QN23 protects from auditory cell oxidative injury and noise-induced hearing loss

Oxidative stress is a key pathogenic mechanism in noise-induced hearing loss, occurring when the production of free radicals in the cochlea overwhelms its antioxidant defenses. Thus, antioxidant molecules, including N-acetyl-L-cysteine, acetyl-L-carnitine, resveratrol, HPN-07 and 4-OHPBN nitrones have been explored as otoprotective agents with limited success. A novel quinolyl-nitrone derivative QN23 has been shown to suppress oxidative stress in ischemic stroke. In this study, we show that QN23 was not ototoxic and protected from oxidative stress both in vitro in the cochlear HEI-OC1 cell line and in vivo in mice. QN23 increased HEI-OC1 cell survival after H₂O₂-induced oxidative stress showing better effectiveness than N-acetyl-L-cysteine. Systemic administration of QN23 in mice was well-tolerated and significantly reduced acute auditory threshold shifts one day post-noise exposure. The protective effects of QN23 were dose- and time-dependent, with optimal results observed when administered twice daily for three days, starting one hour prior to noise exposure. This protection was associated to the duration of the treatment. QN23 normalized the expression of cochlear genes associated with oxidative stress and inflammation such us Nrf2, Hmox1, Nqo1, Nlrp3, Tnfa, Il1b, Dusp1 and Kim1, among others, counteracting immediate noise-induced molecular alterations. These results suggest that QN23 effectively mitigates cochlear oxidative damage and that early intervention can block critical molecular changes induced by noise, thereby preserving hearing.