Abstract
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 quinolylnitrone 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 H(2)O(2)-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 1 day postnoise exposure. The protective effects of QN23 were dose- and time-dependent, with optimal results observed when administered twice daily for 3 days, starting 1 h prior to noise exposure. This protection was associated with the duration of the treatment. QN23 normalized the expression of cochlear genes associated with oxidative stress and inflammation, such as 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.