Targeting retinoid acid metabolic pathway to treat noise-induced hearing loss

Acoustic traumatic injury to the cochlea could result in permanent hearing impairment and affect a patient’s daily life, including that of injured veterans. Several pharmacological interventions have been proposed for noise-induced hearing loss (NIHL) treatment; however, none have been shown to be widely effective without serious side effects. In most cases, many of the hair cells and their innervating neurons that survive the initial acoustic injury later degenerate. Much of this later loss of hair cells and neurons is driven by inflammation in the inner ear. Reducing inflammation may thus promote the survival of cochlear tissue needed to preserve auditory function. Retinoic acid (RA), an active derivative of vitamin A, is critical for inflammation and neuronal regeneration under pathological conditions. In this proposal, we will target RA metabolism pathways to reduce the inflammation after acoustic injury. Specifically, we will inhibit RA degradation by DX308 so that there will be more endogenous RA to reduce inflammation and enhance regeneration. We will apply DX308 for 7 days before or after noise exposure in mice to see whether this drug reduces the hearing loss. Sensitive methods will assess the pathological consequence of the NIHL and the protective effects of the DX308 treatment. If successful, it should provide a potential novel therapeutic approach in NIHL treatment. In the long-term, these studies will provide a scientific rationale for further clinical trials of DX308 for the treatment of NIHL and lead to a new treatment strategy that could benefit affected veterans and their families.