S-Methylthiocitrulline, a neuronal nitric oxide synthase inhibitor, protects against malonate and MPTP neurotoxicity.

Nitric oxide may be a key mediator of excitotoxic neuronal injury in the central nervous system. In the present experiments we found that S-methylthiocitrulline, a relatively selective neuronal nitric oxide synthase (NOS) inhibitor, produced significant neuroprotection against striatal lesions produced by malonate, and the protection was reversed by l-arginine but not by d-arginine. S-Methylthiocitrulline attenuated malonate-induced increases in 2,3- and 2,5-dihydroxybenzoic acid/salicylate and 3-nitrotyrosine/tyrosine, which may be a consequence of peroxynitrite generation. S-Methylthiocitrulline significantly protected against 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced depletions of dopamine, 3, 4-dihydroxyphenylacetic acid, and homovanillic acid. These findings provide further evidence that relatively selective inhibitors of neuronal NOS are neuroprotective in vivo and that they might therefore be useful in the treatment of neurodegenerative diseases.