Nitric oxide: role in neurotoxicity

1. Nitric oxide (NO) is a novel neuronal messenger molecule which interacts with surrounding neurones, not by synaptic transmission but by diffusion between cells. 2. NO is produced following stimulation of the enzyme, NO synthase (NOS). After synthesis, NO exerts its biological actions by diffusion to the site of action. Therefore, the way to regulate the physiological actions of NO is to regulate NOS. 3. NOS is activated by the influx of calcium from glutamate-activated N-methyl-D-aspartate receptors. Overactivation of these receptors leads to overproduction of NO and neuronal cell death. 4. NOS can be regulated at the catalytic site, at the flavo-proteins, at the calmodulin site and by phosphorylation. 5. In excess, NO is toxic to neurones. This toxicity is mediated largely by an interaction with the superoxide anion, presumably through the generation of the oxidant, peroxynitrite. 6. NO or peroxynitrite-mediated neuronal injury involves the activation of the nuclear protein, poly(ADP-ribose)synthetase.