N-Acetylcysteine Synergizes with Oseltamivir in Protecting Mice from Lethal Influenza Infection

Abstract

Many studies have shown that oxidative stress is important in the pathogenesis of pulmonary damage during influenza virus infections. Antioxidant molecules are therefore potentially useful against viral infection. Our previous studies show that N-acetylcysteine (NAC) has a protective effect in a model of lethal influenza infection in mice. NAC administration significantly decreased the mortality in infected mice. Further studies have demonstrated that NAC enhanced survival in combination with the antiviral agent ribavirin. In the present study, we report the effect of combined treatment with NAC and Oseltamivir, clinically used in the treatment and prevention of influenza virus infection, in a murine model of lethal influenza infection. NAC was given as a single daily dose of 1000 mg/kg starting from 4 h before infection and until day 4 after infection; Oseltamivir was given twice daily at dose of 1 mg/kg/die for 5 days, starting from 4 h before infection. End-point evaluation was 21-days survival. NAC alone was slightly effective (20%), since a suboptimal treatment was used. Survival increased to 60% with Oseltamivir and to 100% with Oseltamivir and NAC used in combination. Since NAC alone does not show any antiviral action, the present findings suggest that antioxidant therapy increase survival by an improvement in host defense mechanisms, and/or by a direct antioxidant effect against oxidative stress associated with viral infection. Our studies demonstrate the effectiveness of combining agents acting through different mechanisms, such as antiviral drugs oseltamivir and the antioxidant NAC, indicating a possible advantage of combining the two treatments.