Nuevas estrategias para la prevención de la pérdida auditiva neurosensorial en el ratón: ácidos grasos omega-3 y dendrogenina B

Résumé

Sensorineural hearing loss is one of the main causes of impairment worldwide. It presents a multifactorial etiology that includes genetic and environmental factors. In spite of their critical consequences at medical, occupational and social level, effective treatments are not available; consequently, research in new therapies is essential. Disturbances of the methionine cycle in the cochlea give rise to oxidative stress and hypoacusis, in man and mouse, and therefore, this cycle represents a potential therapeutic target. Several epidemiological studies evidence that nutrition is essential in hearing loss prevention and that ingestion of omega-3 fatty acids have benefits in inflammation and oxidative stress. Otherwise, an intervention with small molecules like dendrogenins, which have shown in vitro neuroprotective activity, provides a novel pharmaceutical approach to treat hearing loss. In this study, a mouse model has been used to i) characterize changes in the cochlear methionine cycle with ageing and after noise exposure, ii) to evaluate the effect of omega-3 fatty acids supplementation in the treatment of age-related hearing loss, iii) to study the effect of dendrogenin AF243 in the treatment of noise induced hearing loss. The results from this study suggest that: i) cochlear expression of Bhmt, Bhmt2 and Cbs increases with age, however Mtr, Mat2a, Mat2b and Ahcy expression decreases. Furthermore, noise exposure provokes an increase in ABR hearing thresholds associated with Bhmt and Bhmt2 decrease expression and an increase in BHMT2 protein and expression of pro-inflammatory cytokines Il1b and Il6. ii) omega-3 supplementation significantly reduces the increase in hearing thresholds associated with ageing together with the cochlear expression of pro-inflammatory cytokines in the cochlea. Moreover, omega-3 supplementation modulates methionine cycle genes expression, particularly Bhmt and Cbs. iii) Noise induced hearing loss is partially protected by a single topical administration of AF243. However, systemic sustained treatment of AF243 before and after noise exposure obviously improves hearing thresholds and expression of pro-inflammatory and cellular damage markers. In conclusion, cochlear methionine cycle is modulated by age and before noise exposure in mice, and therefore suggests a potential therapeutic target. In a mouse model, omega-3 fatty acid supplementation and AF243 dendrogenin have demonstrated a protective role against the development of age-related and noise induced hearing loss, respectively.