Antidystonic efficacy of nitric oxide synthase inhibitors in a rodent model of primary paroxysmal dystonia

1 In a hamster model (genetic symbol dt(sz)) of primary paroxysmal non-kine siogenic dystonic choreoathetosis, recent studies have shown beneficial eff ects of glutamate and dopamine receptor antagonists. Nitric oxide (NO), syn thesized from L-arginine by NO synthase in response to glutamate receptor a ctivation, elicits cyclic CMP and modulates glutamate-mediated processes an d striatal dopamine release. 2 Therefore, the effects of NO synthase inhibitors and of L-arginine on sev erity of dystonia were investigated in dt(sz) hamsters in which dystonic at tacks, characterized by twisting movements and postures, can be induced by stress. 3 The NO synthase inhibitors N-G-nitro-L-arginine (L-NNA), N-G-nitro-L-argi nine methyl ester (L-NAME) and 7-nitroindazole significantly reduced the se verity of dystonia. At antidystonic effective doses neither L-NNA nor L-NAM E caused observable side effects, whereas 7-nitroindazole exerted moderate reduction of locomotor activity. 4 The antidystonic effect of L-NAME was reversed by co-administration of th e NO precursor L-arginine. However, L-arginine administered alone did not e xert any effect on severity of dystonia. 5 Cerebellar cyclic GMP levels in brains of mutant hamsters in comparison t o non-dystonic control hamsters did not significantly differ, but the cereb ellar cyclic CMP levels tended to be increased in dt(sz) hamsters during a dystonic attack. L-NAME significantly decreased the cerebellar cyclic GMP l evels in both dt(sz) and control hamsters. 6 Although an overproduction of NO is probably not critically involved in t he pathogenesis of paroxysmal dystonia, it may contribute to the manifestat ion of dystonic attacks, as indicated by the antidystonic effects of NO syn thase inhibitors. 7 Peripheral side effects may limit the clinical use of NO synthase inhibit ors, but more selective inhibitors of the neuronal NO synthase should be co nsidered as interesting candidates for the treatment of paroxysmal dystonia .