Nitric oxide synthases: targets for therapeutic strategies in neurologicaldiseases

Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumat ic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's dis ease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in coope ration with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurio us effects of NO derived from neuronal or inducible isoforms. New neuroprot ective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400W) isoforms or with compounds com bining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The ef ficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.