Provoking neuroprotection by peroxynitrite

Peroxynitrite, the product of the reaction between nitric oxide and superoxide, is spontaneouly formed within most mammalian cells under physiological conditions. Initial work addressing the pathophysiology of peroxynitrite afforded the generally accepted notion that this compound would be the long-term neurotoxic nitric oxide-derivative. However, over the past six years a number of interesting studies have reported direct in vivo and in vitro evidence that, at nanomolar-low micromolar concentrations, peroxynitrite is actively involved in triggering cellular survival signals. Most such evidence came from studies demonstrating protection against myocardial ischemia-reperfusion injury and neuronal apoptosis. Although full elucidation of the precise mechanism responsible for such protection still requires further research, peroxynitrite has been shown to promote the nitration and/or phosphorylation of regulatory sites at tyrosine kinase receptors coupled to well-known antiapoptotic pathways, such as those involving phosphoinositide 3-kinase/Akt or mitogen-activated protein kinases. In addition, peroxynitrite-mediated transient protection of neurons against apoptotic death is associated with rapid stimulation of glucose metabolism and glutathione regeneration. In view of the potential cytoprotective function of peroxynitrite, further studies specifically focused on elucidating the possible therapeutic potential of peroxynitrite are sure to appear.