FIG. 15.

Roles of NO and peroxynitrite in the pathophysiology of stroke. Brain ischemia and reperfusion leads to transient stimulation of the activity of endothelial NO synthase (eNOS), resulting in brief increases in endothelial NO generation, associated with neuroprotective actions in stroke. In parallel, ischemic energy depletion and oxidant (ROS) production triggers the release of glutamate, which results in neuronal calcium overload from extracellular (activation of calcium channels) and intracellular (phosphoinositol-3-kinase-endoplasmic reticulum signaling) sources. Calcium overload results in prolonged synthesis of NO, due to stimulated activity of the neuronal isoform of NO synthase (nNOS). Enhanced NO generation also depends on the induced expression of inducible NOS (iNOS) in various types of reactive inflammatory cells, upon the activation of several cell signaling pathways (HIF-1, STAT-3, and NFκB) in response to hypoxia, cytokines, oxidants, and glutamate. During the same period of time, superoxide production is enhanced due to uncoupling of eNOS, mitochondrial dysfunction, and the stimulated activity of NADPH oxidase, xanthine oxidase, and cyclooxygnease-2 (COX-2). Formation of peroxynitrite is then markedly favored, damaging lipids, proteins, DNA, and triggering the activation of poly(ADP-ribose) polymerase (PARP), which all contribute significantly to neurotoxicity in stroke.