Ischemia-Induced Shift of Inhibitory and Excitatory Amino Acids from Intra- to Extracellular Compartments

Abstract

Brain ischemia was induced for 10 or 30 min by clamping the common carotid arteries in rabbits whose vertebral arteries had previously been electrocauterized. EEG and tissue content of high energy phosphates were used to verify the ischemic state and to evaluate the degree of postischemic recovery. Extracellular levels and total contents of amino acids were followed in the hippocampus during ischemia and 4 h of recirculation. At the end of a 30-min ischemic period, GABA had increased 250 times, glutamate 160 times, and aspartate and taurine 30 times in the extracellular phase. The levels returned to normal within 30 min of reflow. A delayed increase of extracellular phosphoethanolamine and ethanolamine peaked after 1–2 h of reflow. Ten minutes of ischemia elicited considerably smaller but similar effects. With respect to total amino acids in the hippocampus, glutamate and aspartate decreased to 30–50% of control while GABA appeared unaffected after 4 h of reflow. Alanine, valine, phenylalanine, leucine, and isoleucine increased severalfold. The importance of toxic extracellular levels of excitatory amino acids, as well as of high extracellular levels of inhibitory amino acids, are considered in relation to the pathophysiology of neuronal cell loss during cerebral ischemia.

Redistribution of Glutamate and Glutamine in Slices of Human Neocortex Exposed to Combined Hypoxia and Glucose Deprivation in vitro

“…Our findings suggest that neuronal somata con tribute significantly to the increased extracellular concentration of glutamate observed during isch emia (Benveniste et al, 1984;Hagberg et al, 1985;Korf et al, 1988;Mitani et al, 1991). In contrast, it appears that glutamate accumulates in glial cells fol lowing glucose deprivation and hypoxia.…”

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

“…Acute cerebral insults such as ischemia and brain trauma are associated with excessive release and extracellular accumulation of the neurotransmitter glutamate (1), leading to persistent activation of glutamate receptors and neurodegeneration (2)(3)(4)(5). The glutamate receptor mediated increase of reactive oxygen species (ROS) (6-8) may be a triggering event in the excitotoxic cell death (9)(10)(11)(12).…”

“…The latter two were included because previous studies by others and us have shown that these amines are released after NMDAreceptor stimulation and other insults (4,(39)(40)(41)(42)(43).…”

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

“…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-…”