Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats

The role of nitric oxide (NO) in the pathogenesis of Viral encephalitis was investigated by using an experimental model of herpes simplex virus type 1 (HSV-1) encephalitis in Lewis rats. The expression of inducible NO synthas e (iNOS) mRNA determined by Northern blotting was observed first in the olf actory bulb and the brain stem on day 5 after intranasal inoculation of HSV -1, and thereafter iNOS mRNA was detected in other brain regions, i.e., cer ebrum and cerebellum. In Various parts of the brain, excessive NO productio n was identified by electron spin resonance spectroscopy. The temporal and spatial patterns of iNOS expression coincided with those of viral propagati on, as demonstrated by polymerase chain reaction for HSV-1 gene expression as well as by the plaque-forming assay. Immunohistochemical study determine d that iNOS was localized mainly in monocyte-derived macrophages. Treatment of virus-infected animals with the NOS inhibitor N-omega-monomethyl-L-argi nine (L-NM MA), but not N-omega-monomethyl-D-arginine, significantly amelio rated not only clinical symptoms such as paralysis and seizures but also mo rtality. Virus yield from brain tissue was not affected by L-NMMA treatment . It is of interest that increased expression of the antioxidant enzyme hem e oxygenase-1 was observed in the HSV-1-infected brain; this increased expr ession was strongly inhibited by L-NMMA treatment. These data suggest that the high level of NO produced by iNOS is a pathogenic factor in HSV-1-induc ed encephalitis in rats. (C) 1999 Academic Press.