The double-edged role of nitric oxide in brain function and superoxide-mediated injury.
Fetal ischemia or hypoxia can lead to cerebral palsy, mental retardation and epilepsy. We propose that the production of nitric oxide and oxygen radicals by neurons when ischemic or hypoxic brain is reperfused may contribute to cerebral injury. Ischemia will depolarize neuronal membranes causing the synaptic discharge of the excitatory neurotransmitter glutamate, which in turn opens the voltage-dependent, N-methyl-D-aspartic acid-specific glutamate receptor/ionophore, allowing calcium to accumulate in the neuron. Calcium in turn activates an oxygen-dependent neuronal nitric oxide synthetase, which oxidizes arginine to produce nitric oxide (.NO) when oxygen is readmitted to brain by reperfusion. Nitric oxide reacts with the oxygen radical superoxide (O2-), also produced by reperfusion, to form peroxynitrite (ONOO-). Peroxynitrite can diffuse for several micrometers before decomposing to form the powerful and cytotoxic oxidants hydroxyl radical and nitrogen dioxide. The hypothesis is consistent with available evidence on the protective action of glutamate antagonists and of oxygen radical scavengers for limiting cerebral infarction following focal ischemia.
Department of Anesthesiology, University of Alabama, Birmingham.
J S
JS
Beckman
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology*; D005260:Female; D005311:Fetal Hypoxia / Q000209:etiology*; D005609:Free Radicals; D006801:Humans; D007231:Infant, Newborn; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D011247:Pregnancy; D015427:Reperfusion Injury / Q000209:etiology*; D013481:Superoxides / Q000378:metabolism*
D000596:Amino Acids; D001685:Biological Factors; D005609:Free Radicals; D018377:Neurotransmitter Agents; D013481:Superoxides; C056250:epithelium-derived relaxant factor; D009569:Nitric Oxide