Resveratrol and N-acetylcysteine combined treatment modulates the expression of oxidative stress response genes and ameliorate cochlear damage in a ototoxicity rat model

Resumen del trabajo presentado al 1st International Symposium on Inner Ear Therapies, celebrado en Marrakech del 1 al 3 de noviembre de 2017.
[Background]: Aminoglycoside antibiotics are widely used in medicine but they show ototoxic side-effects. The generation of reactive oxygen species is a central element in ototoxicity, leading to oxidative stress, inflammation and ultimately activation of caspase-dependent apoptosis. Several antioxidants have been used independently in clinical trials against ototoxicity, with positive but limited effects. The combination of antioxidant drugs with complementary mechanisms of action is a novel approach that could provide stronger ROS scavenging potentiate the otoprotection and prevent the oxidation of the drugs themselves. [Objective]: Toevaluate the protective effect of a treatment with resveratrol plus N-acetylcysteine (NAC) on the ototoxic actions of kanamycin and furosemide in the rat. [Methods]: Resveratrol (10 mg/kg) and NAC (400 mg/kg) were administered together intraperitoneally to male 2 monthold Wistar rats on 5 consecutive days. The second day, a concentrated solution of kanamycin and furosemide was placed unilaterally on the round window by bullostomy to induce ototoxicity. Auditory brainstem responses were registered before and 5, 16 and 23 days after the beginning of the treatment. Cochlear samples were taken at day 5 and 23 to analyze oxidative balance and inflammation related genes by targeted PCR arrays or RT-qPCR, respectively. The cytoarchitecture and the presence of apoptosis, oxidative stress and inflammation markers were evaluated in cochlear sections. [Results and Conclusions]: Co-administration of resveratrol plus NAC reduced the threshold shifts induced by ototoxic drugs, although this protective effect fades after the cessation of the treatment. The treatment modulated the expression of genes involved in the cellular oxidative (Gpx1, Sod1, Ccs and Noxa1) and inflammatory (Il1b, Il4, Mpo and Ncf) responses to injury.
FP7-PEOPLE-2013-IAPP TARGEAR and Spanish MINECO-FEDER/SAF2014-53979-R to IVN, and FEDER-ERDF FIS PI10/00394 to TR. SM holds a CIBERER ISCIII researcher contract. SP and JMBM are supported by a MINECO/BES-2015-071311 predoctoral fellowship and contract, respectively. RMV held CSIC predoctoral contract. SP and MM were further supported by MouseAge COST-BM1402 and by CIBERER ISCIII.