Differences in ischemia-induced accumulation of amino acids in the cat cortex.

Abstract

It is well established that excitatory amino acid neurotransmitters are extensively liberated during ischemia and that they have neurotoxic properties contributing to neuronal injury. To study changes in the liberation of excitatory and other amino acids during cerebral ischemia, we measured their extracellular concentrations and related them to blood flow levels and electrophysiologic activity (electrocorticogram and auditory evoked potentials) before and for up to 2 hours after multiple cerebral vessel occlusion in 14 anesthetized cats. Blood flow levels between 0 and 43 ml/100 g/min were reached. Concentrations of the excitatory amino acid neurotransmitters increased most (aspartate 10-fold, glutamate 30-fold, and -y-aminoburyric acid 300-fold compared with control values) below a blood flow threshold of 20 ml/100 g/min. The total power of the electrocorticogram and the amplitude of the auditory evoked potentials were affected below the same blood flow threshold. In contrast, concentrations of the nontransmitter amino acids taurine, alanine, asparagine, serine, and glutamine increased 1.5-5-fold as blood flow decreased, while concentrations of the essential amino acids phenylalanine, valine, leucine, and isoleucine did not change during cerebral ischemia. The great increases in concentrations of the excitatory amino acid neurotransmitters below a blood flow threshold close to that for functional disturbance is in accordance with the role of these amino acids in ischemic cell damage. Their release at blood flow levels compatible with cell survival and the increase in their concentrations with severity and duration of cerebral ischemia imply that excitotoxic antagonists may have potential as therapeutic agents. (Stroke

Changes in Amino Acid Neurotransmitters and Cerebral Blood Flow in the Ischemic Penumbral Region following Middle Cerebral Artery Occlusion in the Rat: Correlation with Histopathology

“…In models of focal ischemia in which the scalp and cranium are opened, brain temperature de creases during ischemia unless a method of main taining brain temperature is employed (Morikawa et aI., 1992). Thus, ischemic brain temperature in the study of Shimada et al (1990) may possibly have been lower than in the present study. This may have caused the CBF threshold for glutamate release to have been shifted to lower levels.…”

“…As others have shown a good linear correspondence between absolute CBF and relative CBF measured by laser-Doppler flowmetry (Dirnagl et aI., 1989), it is reasonable to infer that the ischemic CBF threshold value of 48% (as defined statistically) for neurotransmitter release in our study was some what higher than in the study of Shimada et al (1990). However, our subgroup analysis (Fig.…”

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

“…However, these changes are much less severe in the ischemic penumbra (Lipton, 1999). Extracellular glutamate concentrations in penumbral tissue are elevated to a lesser extent than in the core (Wang et al, 2001), estimated at 30-50 µM in different studies (Shimada et al, 1990;Wahl et al, 1994;Morimoto et al, 1996).…”

Factors affecting excitatory amino acid release following severe human head injury

“…[3,6,10,11,17,22,49] Following the comparatively recent discovery of this role, it has become a focus of major neuroscientific interest because of its potential role in the causation of both acute and chronic neuronal damage. In 1983, Rothman and Olney[46] proposed the "excitotoxic" hypothesis.…”

“…[3,6,11,22,23,43,49] In these models, a variety of drugs that block the effects of glutamate both presynaptically and at postsynaptic receptor sites have reduced both ischemic brain damage and glutamate release. [5,7,12,20,21,24,25,29,32,33,36,40,53,55,56] There are now several Phase II and Phase III trials in progress to evaluate the efficacy of glutamate antagonist drugs in both neurotrauma and stroke.…”