The Role of Nitric Oxide in the Pathogenesis of Virus-Induced Encephalopathies

Abstract

The mechanism by which virus infections of the central nervous system (CNS) cause neuronal damage are understood in only a few viral CNS diseases in which there is evidence that the virus directly destroys its target cells. In many other cases of virus-induced encephalopathy, the virus does not directly destroy neural tissue but causes indirect damage by altering neuronal functions (Fu et al. 1993; Lipkin et al. 1988a,b) or by triggering cell-mediated responses within the CNS (Byrne and Oldstone 1984; Carbone et al. 1988; Doherty et al. 1976). Soluble factors such as proinflammatory cytokines, proteases, free radicals, and neurotoxins produced by immune cells are thought to play an important role in the process of neuronal destruction (Shankar et al. 1992; Koprowski et al. 1993). It is believed that proinflammatory cytokines in particular are exceptionally important in the process of neuronal destruction (Selrnaj 1992). It has been shown that cytokines can have direct cytotoxic effects. For example, the intracisternal challenge of interleukin-1 (IL-1) or tumor necrosis factor (TNF) in rats induced meningitis and blood brain barrier damage (Quagliarello et al. 1991). Recently, attention has focused on the possibility that reactive nitrogen intermediates generated by nitric oxide synthases (NOS) directly damage neural tissue. Both the constitutive form of NOS (cNOS), and the inducible calcium-independent NOS (iNOS) are thought to play a role in the process of neuronal damage (Koprowski et al. 1993; Murphy et al. 1993).