Glutamate efflux from human cerebrocortical slices during ischemia: vesicular-like mode of glutamate release and sensitivity to A(2A) adenosine receptor blockade.

Abstract

Glutamate extracellular accumulation is an early event in brain ischemia triggering excitotoxic neuron damage. We have investigated how to control the glutamate efflux from human cerebrocortical slices superfused in conditions simulating an acute ischemic insult (oxygen and glucose deprivation). The efflux of previously accumulated [3H]D-aspartate or endogenous glutamate increased starting 18 min after exposure to ischemia and returned almost to basal values in 6 min reperfusion with standard medium. Superfusion with Ca2+-free, EGTA (0.5 mM)-containing medium or with medium containing tetrodotoxin (TTX; 0.5 microM) inhibited the ischemia (24 min)-evoked [3H]D-aspartate efflux by about 50% and 65%, respectively. The ischemia (24 or 36 min)-evoked efflux of [3H]D-aspartate or endogenous glutamate was reduced at least 40% by the adenosine A(2A) receptor antagonist SCH 58261 (1 microM); the compound was effective when added up to 15 min after exposure to ischemia. No effect of SCH 58261 on the ischemia-evoked [3H]D-aspartate was found in Ca2+-free, EGTA-containing medium. To conclude, a significant component of the ischemia-evoked glutamate efflux in human cerebrocortical slices seems to occur by a vesicular-like mechanism. Endogenously released adenosine is likely to activate A(2A) receptors that enhance vesicular-like glutamate release during ischemia; A(2A) receptor antagonists would deserve consideration for their neuroprotective potential.

• Authors: Manuela Marcoli, Andrea Bonfanti, Paola Roccatagliata, Greta Chiaramonte, Ennio Ongini, Maurizio Raiteri, Guido Maura
• Journal: Neuropharmacology (Neuropharmacology) Vol. 47 Issue 6 Pg. 884-91 (Nov 2004) ISSN: 0028-3908 [Print] England
• PMID: 15527822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
• Adenosine A2 Receptor Antagonists
• Anesthetics, Local
• Neuroprotective Agents
• Pyrimidines
• Triazoles
• Aspartic Acid
• Glutamic Acid
• Tetrodotoxin
• Glucose
• Calcium

Topics

• Adenosine A2 Receptor Antagonists
• Adult
• Aged
• Anesthetics, Local (pharmacology)
• Aspartic Acid (metabolism)
• Brain Ischemia (metabolism)
• Calcium (physiology)
• Cerebral Cortex (drug effects, metabolism)
• Female
• Glucose (deficiency, physiology)
• Glutamic Acid (metabolism)
• Humans
• In Vitro Techniques
• Male
• Middle Aged
• Neuroprotective Agents (pharmacology)
• Pyrimidines (pharmacology)
• Reperfusion Injury (pathology)
• Synaptic Vesicles (drug effects, metabolism)
• Tetrodotoxin (pharmacology)
• Triazoles (pharmacology)