Enhanced release of synaptic glutamate underlies the potentiation of oxygen-glucose deprivation-induced neuronal injury after induction of NOS-2.
Reactive nitrogen oxide species (RNOS) may contribute to the progression/enhancement of ischemic injury by augmentation of glutamate release, reduction of glutamate uptake, or a combination of both. Consistent with this, induction of nitric oxide synthase (NOS-2) in murine neocortical cell cultures potentiated neuronal cell death caused by combined oxygen-glucose deprivation in association with a net increase in extracellular glutamate accumulation. However, uptake of glutamate via high affinity, sodium-dependent glutamate transporters was unimpaired by induction of NOS-2 under either aerobic or anaerobic conditions. Further, blocking possible routes of extra-synaptic glutamate release with NPPB [5-nitro-2-(3-phenylpropylamino)-benzoic acid], a volume-sensitive organic anion channel blocker, or TBOA (d,l-threo-beta-benzyloxyaspartate), an inhibitor of glutamate transport, exacerbated rather than ameliorated injury. Finally, treatment with riluzole or tetanus toxin attenuated the enhancement in both glutamate accumulation and oxygen-glucose deprivation-induced neuronal injury supporting the idea that increased synaptic release of glutamate underlies, at least in part, the potentiation of neuronal injury by RNOS after NOS-2 induction.
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030-3401, USA.
Aniruddha S
AS
Vidwans
Sandra J
SJ
Hewett
D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005110:Extracellular Space / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009579:Nitrobenzoates / Q000494:pharmacology; D019782:Riluzole / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D013744:Tetanus Toxin / Q000494:pharmacology
D018696:Neuroprotective Agents; D009579:Nitrobenzoates; D013744:Tetanus Toxin; C120673:benzyloxyaspartate; D001224:Aspartic Acid; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D018698:Glutamic Acid; D019782:Riluzole; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005947:Glucose