MECHANISMS OF GLUTAMATE AND ASPARTATE RELEASE IN THE ISCHEMIC RAT CEREBRAL-CORTEX

Citation
Jw. Phillis et Mh. Oregan, MECHANISMS OF GLUTAMATE AND ASPARTATE RELEASE IN THE ISCHEMIC RAT CEREBRAL-CORTEX, Brain research, 730(1-2), 1996, pp. 150-164
Citations number
69
Categorie Soggetti
Neurosciences
Journal title
ISSN journal
00068993
Volume
730
Issue
1-2
Year of publication
1996
Pages
150 - 164
Database
ISI
SICI code
0006-8993(1996)730:1-2<150:MOGAAR>2.0.ZU;2-X
Abstract
Elevated levels of glutamate and aspartate have been implicated in the pathogenesis of neural injury and death induced by ischemia. The mech anism(s) whereby they escape into the extracellular environment have b een a subject of controversy. This study evaluated the contribution of phospholipases and protein kinases to ischemia-evoked glutamate and a spartate release from the ischemic/reperfused rat cerebral cortex. Cha nges in the extracellular levels of these amino acids during four-vess el occlusion elicited global cerebral ischemia were examined using a c ortical cup technique. Ischemia-evoked amino acid release was compared in control vs. drug treated animals, in which selective inhibitors of phospholipases and protein kinases were applied topically onto the ce rebral cortex. The phospholipase inhibitors tested included 4-bromophe nacyl bromide, a non-selective inhibitor; 7,7-dimethyleicosadienoic (D EDA), an inhibitor of secretory type phospholipase A(2) (PLA(2)); AACO CF(3), an inhibitor of the Ca2+-dependent cytoplasmic form of PLA(2), HELSS, which inhibits a Ca2+-independent cytoplasmic PLA(2), and U7312 2, a selective inhibitor of phospholipase C (PLC). All five phospholip ase inhibitors significantly attenuated glutamate and aspartate releas e into the extracellular milieu, indicating the possibility that sever al forms of the enzyme are likely to be involved. The protein kinase C (PKC) inhibitor, chelerythrine chloride, also reduced excitatory amin o acid efflux, whereas the PKC activator phorbol 12-myristate 13-aceta te (PMA) enhanced their release. The non-selective kinase inhibitor, s taurosporine: and H-89, which selectively inhibits protein kinase A, d id not reduce ischemia-evoked amino acid efflux. These results suggest that ischemia-evoked release of the excitatory transmitters amino aci ds is a result, in part, of the activation of phospholipases A, and C, with PKC involvement in the transduction process. Destabilization and deterioration of the plasma membrane, as a consequence of phospholipi d hydrolysis, may allow these transmitter amino acids to diffuse down their concentration gradients into the extracellular fluid.