Inhibition of Japanese encephalitis virus infection by diethyldithiocarbamate is independent of its antioxidant potential

Abstract

Diethyldithiocarbamate (DDTC), a low molecular weight dithiol, has been described as an immunomodulator and modifier of diverse biological actions in human and animal models, and has also been shown to be effective in several disease conditions. Therefore, we studied the therapeutic aspect of DDTC in providing inhibition of Japanese encephalitis virus (JEV) infection. DDTC tested at various doses (10-100 micromol/kg) revealed that administration at low concentration (10 micromol/kg; i.p.) on alternate days prolonged the average survival time (AST) of mice infected with lethal dose of JEV (102 LD50, i.c.) and delayed progression of the disease. The low dose also provided > 80% survival in sub-clinical (10(5) LD50, i.c.) JEV infection. Administration of DDTC to JEV-infected mice enhanced the inducible nitric oxide synthase (iNOS) activity in brain and level of serum tumour necrosis factor-alpha (TNF-alpha). We have recently demonstrated the production of nitric oxide (NO) via induction of iNOS activity is meditated by circulating macrophage-derived factor (MDF), which may be responsible for the delayed progression of the disease. DDTC-mediated inhibition of JEV is believed to involve the augmentation of protective role of MDF as evidenced by the observation that pretreatment with anti-MDF antibody significantly decreased the AST of mice and together with the inhibition of iNOS activity. Interestingly, DDTC alone did not stimulate iNOS and TNF-alpha in mock-infected normal mice. These results show that DDTC may have a possible therapeutic role during JEV infection.