Expression and potential role of inducible nitric oxide synthase in the central nervous system of Theiler's murine encephalomyelitis virus-induced demyelinating disease

Intracerebral inoculation of susceptible strains of mice with Theiler's mur ine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. We examined the pathogenic roles of nitric oxide (NO) and inducib le NO synthase (iNOS) in TMEV-induced demyelinating disease (TMEV-IDD). The presence of iNOS was confirmed in the spinal cords of TMEV-infected mice u sing immunohistochemical staining with anti-iNOS antibody on day 0 (control ) and days 15, 30, 60, and 120, Aminoguanidine (AG), a specific inhibitor o f iNOS, was injected intraperitoneally (ip) on 1, 3, 5, 8, 10, and 12 days post-TMEV inoculation as induction phase or 15, 17, 19, 22, 24, and 26 days as effector phase. Control animals in each experiment received phosphate-b uffered saline (PBS) ip at similar time intervals. Few iNOS-positive cells were observed in the spinal cords of naive SJL/J mice. In the early phase ( day 15) of TMEV-IDD, an increase of iNOS-positive cells was detected in the leptomeninges and perivascular space of the spinal cords. The number of iN OS-positive cells was increased and reached its peak on day 60, when histol ogy of the animals showed peak infiltration with inflammatory cells. The cl inical course of TMEV-IDD on each day postintracerebral infection was signi ficantly reduced in mice treated with AG in the effector phase, and there w as no significant difference between mice treated with AG in induction phas e versus those administered PBS. Thus, NO production via iNOS appears to be a pathogenic factor in the effector phase of TMEV-IDD. (C) 1999 Academic P ress.