Killing of Schistosoma japonicum in the administration of NOS inhibitors and its mechanism

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The effect of nitric oxydase synthase inhibitors in Schistosoma japonicum-infected mice was studied. It was surprisingly found that oral administration of NOS inhibitors, L-NAME and its inactive enantiomer D-NAME, had significant decreasing effects on the worm burden when mice were scarified at 6 week of infection and that D-NAME was more effective than L-NAME in C57BL/6 mice in comprison. In detailed study of D-NAME administration schedules, significant effects were shown when 50-100mg/ml concentration were given, whereas higher concentrations, 200 or 400mg/ml, had no apparent effects. The time of administration examined between 3 to 42 day of infection indicated that the protective effects were apparent when the inhibitor was given during 14-24 day of infection for consecutive 6 days. In the use of several cytokine deficient mice, the effect of the enantiomers interestingly differed with each strain. D-NAME was effective in IFN-g KO mice, while in IL-4 and IL-13KO mice L-NAME showed the effect. Measurement of serum NO levels showed that there was increase in NO in D-NAME-administered C57BL/6, while decreased NO was seen in the administration of L-NAME. In IL-13 KO mice there was exactly reverse relationship, showing increase in NO with L-NAME. Cytokine analysis of splenic cells in protective mice showed a tendency of decrease in IL-10 level, while there was no significant changes in IFN-g level. These observations strongly suggests NO plays a protective role in S.japonicum infection. In whole, our present study indicates several interesting aspects of NOS inhibitors in defensive mechanism of infectious disease.