Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat

Abstract

Summary:The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthe tized cats. Focal cerebral ischemia was produced by per manent occlusion of one middle cerebral artery and the animals were killed 6 h later. The amount of early isch emic damage was assessed in coronal sections at 16 pre determined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.). 30 min before occlusion of the Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. The ac tions of glutamate are mediated via three pharma cologically distinct subtypes of receptor, the no menclature of which reflects the preferred agonist at each receptor subtype viz. the quisqualate-, kainate-, and N-methyl-D-aspartate-(NMDA)-pre ferring receptor (Greenamyre et aL, 1985). Gluta mate has recently been implicated in the patho physiology of cerebral ischemia (Meldrum 1985; Rothman and Olney, 1986). Glutamate itself is neu rotoxic when injected into cerebral tissue (Rothman and Olney, 1986). Cerebral ischemia is associated with a massive increase in extracellular glutamate concentrations (Benveniste et aL, 1984;Hagberg et aL, 1985). Destruction of glutamatergic afferent pathways or intracerebral administration of NMDA receptor antagonists can reduce the early ischemic damage to the hippocampus in cerebral ischemia and the neuronal necrosis which is observed sev eral days after a period of cerebral ischemia or se-

Dihydrolipoate Reduces Neuronal Injury after Cerebral Ischemia

“…The ef-fects of dihydrolipoate in the models of focal cere bral ischemia were not as pronounced as the effects of N-methyl-D-aspartate antagonists reported else where (Gotti et al, 1988;Ozyurt et al, 1988;Park et al, 1988), but our findings show that thiols are able to reduce brain infarction. Assuming that free and sufficiently high plasma concentrations as well as a good CNS penetration can be realized, thiols could become effective tools for the treatment of cerebral ischemia.…”

Effects of Dextromethorphan on Regional Cerebral Blood Flow in Focal Cerebral Ischemia

“…NMDA antagonists have been shown to be effec tive in reducing neuronal damage and edema in var ious animal models of focal cerebral ischemia Ozyurt et al, 1988;Park et al, 1988;Steinberg et al, 1988Steinberg et al, , 1989Buchan, 1990;Goth et al, 1990). In vitro studies with neuronal cell cultures and brain slice preparations have also dem onstrated the ability of NMDA antagonists to pro tect against hypoxic and glutamate cell injury (Choi, 1987;Clark and Rothman, 1987;Goldberg et al, 1987).…”

Repeated Negative DC Deflections in Rat Cortex following Middle Cerebral Artery Occlusion are Abolished by MK-801: Effect on Volume of Ischemic Injury

“…Spreading depression can be blocked by glutamate antagonists (Marrannes et al, 1988), and the same drugs are also able to reduce the size of an infarct following permanent MCA occlusion (Ozyurt et al, 1988;Park et al, 1988;Dirnagl et al, 1990). Inter estingly, the therapeutic effect is not associated with any changes in blood flow (Park et al, 1988(Park et al, , 1989, indicating that the drugs do not interfere with oxygen delivery to the tissue.…”