The role of nitric oxide in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease ch aracterized by selective motor neuronal death. The cause of ALS is unclear, but accumulating evidence, such as the insufficient clearance of glutamate through the glutamate transporter, and the specific distribution of Ca2+-p ermeable AMPA receptors in spinal motor neurons, indicates that glutamate-i nduced neurotoxicity is involved in its pathogenesis. Interestingly, nitric oxide (NO), which has been identified as an endothelium-derived relaxing f actor (EDRF), was found to be a pivotal inducer of glutamate-induced neuron al death. NO is generated by nitric oxide synthase (NOS), of which there ar e three subtypes: neuronal NOS expressed mainly in neurons, inducible NOS i n astroglia, and endothelial NOS in vessels. NO-related toxicity is caused by peroxynitrite, formed by the reaction of NO with superoxide anions, resu lting in the nitration of tyrosine residues in neurofilaments, irreversible inhibition of the mitochondrial respiratory chain, and inhibition of the g lutamate transporter. Clinically, the axonal spheroids of motor neurons are reported to be immunoreactive to anti-nitrotyrosine antibody, and there ar e elevated levels of the metabolites of NO in the cerebrospinal fluid of AL S patients. Since physiologically normal motor neurons express limited amou nts of neuronal NOS, the source of NO is considered to be non-motor neurons expressing neuronal NOS, astroglia expressing inducible NOS, or motor neur ons themselves inducing neuronal NOS. Conversely, neurons containing neuron al NOS are known to be resistant to toxic stimuli, which raises the possibi lity that such neurons are protected by NO. Several mechanisms have been re ported to mediate the NO-related neuroprotection, including cyclic guanosin e 3',5'-monophosphate (cyclic GMP), a downstream product of NO generation. This review summarizes previous studies on NO, focusing on its dual functio ns of neurotoxicity or neu ro protection, and discusses the putative roles of NO in relation to the pathogenesis of ALS.