NMDA receptors increase OH radicals in vivo by using nitric oxide synthase and protein kinase C.
Prolonged activation of brain N-methyl-D-aspartic acid (NMDA) receptors increases intraneuronal (Ca2+) and nitric oxide (NO) synthesis, and may be responsible for neuronal death in acute brain insults and chronic neurodegenerative diseases. NO can be converted in vitro to toxic hydroxyl (OH) radical. Using microdialysis of striatum in awake animals, we found that local NMDA receptor activation increased outflow of OH radicals four-fold. NMDA-stimulated OH production was blocked by inhibitors of nitric oxide synthase (NOS) and protein kinase C (PKC). NMDA receptor-mediated neuronal death may derive from NOS- and PKC-dependent synthesis of OH radicals.
Hammer
B
B
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Parker
W D
WD
Bennett
J P
JP
D000470:Alkaloids / Q000494:pharmacology; D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine / Q000031:analogs & derivatives*
D000470:Alkaloids; D016194:Receptors, N-Methyl-D-Aspartate; C073761:CGP 42700; D017665:Hydroxyl Radical; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin