Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man.

Abstract

1 A wide range of therapeutic strategies has been explored in humans and experimental animals with the aim of improving outcome after brain ischaemia but few have shown convincing clinical benefit. 2 The massive increase in the extracellular concentration of glutamate which occurs in cerebral ischaemia is a key component in the sequence of neurochemical events which leads to neuronal death. Pharmacological blockade of the action of glutamate at the N-methyl-D-aspartate (NMDA) receptor, (the glutamate receptor subtype principally involved in the neurotoxic effects of the amino acid) provides a novel therapeutic approach to cerebral ischaemia. 3 The effects of NMDA receptor antagonists in animal models of focal cerebral ischaemia are uniquely consistent, viz, a marked reduction in the amount of irreversible ischaemic damage irrespective of the species, the model of cerebral ischaemia, when the animals are sacrificed after the ischaemic episode, whether ischaemia is permanent or temporary and followed by reperfusion and which particular NMDA antagonist was employed. 4 NMDA receptor antagonists have marked effects on brain function in normal animals.The balance between these potential adverse effects and the anti-ischaemic efficacy of these drugs will ultimately determine the clinical utility of this class of drugs. 5 The data which are reviewed provide the basis for the current clinical evaluation of NMDA receptor antagonists in stroke and head trauma.

Cerebroprotective effect of a non-N-methyl-D-aspartate antagonist, GYKI 52466, after focal ischemia in the rat.

“…The case for a clinical trial of NMDA antagonists in stroke has been clearly stated. 13 Further studies are required with non-NMDA antagonists before their clinical potential and relative merits compared with NMDA antagonists can be defined.…”

“…2 -8 - 13 Tarnawa and coworkers 14 ' 15 have recently described a novel non-NMDA antagonist, GYKI 52466 (l-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride; molecular weight, 330), which inhibits spinal reflexes in cats but does not potentiate the inhibitory action of y-amino butyrate. Ouardouz and Durand 16 have shown that GYKI 52466 antagonizes the glutamate-but not the NMDA-or KA-induced electrophysiological responses in the abducens motor neurons of the rat.…”

Ginkgolides Protects the Cultured Rat Cortical Cells against Metabolic, Excitotoxic and Oxidative Insults

“…28,29) Glu, through an action on NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors, allows Ca 2+ to enter the cell. 30,31) Glu can The damages were evaluated by the assay of MTT and LDH release from the cultured medium. TG was added simultaneously and 12 hr prior to addition of Glu, and the cells were exposed to 1 mM Glu for 6-12 hr.…”

Prediction of symptomatic vasospasm after subarachnoid hemorrhage by rapidly increasing transcranial Doppler velocity and cerebral blood flow changes.

“…The mean ratio of middle or anterior cerebral artery to internal carotid artery velocities (Aaslid index) was 7.4±0.5 (mean±SEM) in the 15 patients selected for SPECT who had neurological deficit (patients [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. This was significantly greater than the ratio seen in the five patients who did not develop neurological deficit (4.6±0.4, /?=0.003).…”