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.