S-Methylthiocitrulline, a Neuronal Nitric Oxide Synthase Inhibitor, Protects against Malonate and MPTP Neurotoxicity

Abstract

Nitric oxide may be a key mediator of excitotoxic neuronal injury in the central nervous system. In the present experiments we found thatS-methylthiocitrulline, a relatively selective neuronal nitric oxide synthase (NOS) inhibitor, produced significant neuroprotection against striatal lesions produced by malonate, and the protection was reversed byl-arginine but not byd-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 neuroprotectivein vivoand that they might therefore be useful in the treatment of neurodegenerative diseases.