Rosmarinic acid up-regulates the noise activated NRF2/ho-1 pathway and protects against noise-induced injury in rat cochlea

Noise induced hearing loss depends on the progressive increase of reactive oxygen species and lipoperoxidative damage in conjunction with the imbalance of antioxidant defenses. The redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in the regulation of cellular defense against oxidative stress including heme oxygenase-1 (HO-1) activation. In this work we describe a link between cochlear oxidative stress damage, induced by noise exposure, and the activation of Nrf2/HO-1 pathway. In our model, noise induces superoxide production and overexpression of the lipid peroxidation marker, 4-hydroxy-nonenals (4-HNE). To face the oxidative stress, the endogenous defense system is as well activated as shown by the slight activation of superoxide dismutases (SODs). In addition, we also observed the activation of the Nrf2/HO-1 pathway after noise exposure. In doing so, Nrf2 appears to promote the maintenance of cellular homeostasis under stress conditions. However, in this model the endogenous antioxidant system fails to counteract noise-induced cell damage and its activation is not enough effective in preventing the cochlear damage. The herb-derived phenol rosmarinic acid (RA) attenuates noise-induced hearing loss reducing threshold shift and promotes hair cell survival. In fact, RA enhances the endogenous antioxidant defenses as shown by the decreased superoxide production, the reduced expression of 4-HNE and the up-regulation of SODs. Interestingly, RA potentiates the Nrf2/OH-1 signaling pathway as shown by immunohistochemical and western blot analyses. Thus, protective effects of RA are associated with the induction/activation of Nrf2-ARE signaling pathway in addition to RA direct scavenging capability.