The central nervous system inflammatory response to neurotropic virus infection is peroxynitrite dependent

We have recently demonstrated that increased blood-CNS barrier permeability and CNS inflammation in a conventional mouse model of experimental allergi c encephalomyelitis are dependent upon the production of peroxynitrite (ONO O-), a product of the free radicals NO- and superoxide (O-2(-)). To determi ne whether this is a reflection of the physiological contribution of ONOO- to an immune response against a neurotropic pathogen, we have assessed the effects on adult rats acutely infected with Borna disease virus (BDV) of ad ministration of uric acid (UA), an inhibitor of select chemical reactions a ssociated with ONOO-. The pathogenesis of acute Borna disease in immunocomp etent adult rats results from the immune response to the neurotropic BDV, r ather than the direct effects of BDV infection of neurons. An important sta ge in the BDV-specific neuroimmune response is the invasion of inflammatory cells into the CNS. UA treatment inhibited the onset of clinical disease, and prevented the elevated blood-brain barrier permeability as well as CNS inflammation seen in control-treated BDV-infected rats. The replication and spread of BDV in the CNS were unchanged by the administration of UA, and o nly minimal effects on the immune response to BDV Ags were observed. These results indicate that the CNS inflammatory response to neurotropic virus in fection is likely to be dependent upon the activity of ONOO- or its product s on the blood-brain barrier.