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(Accepted May 12, 2001)
Exposure of guinea pig brain slices to low concentrations (10 mM) of NMDA caused decreases in PCr and ATP within 30 min, with a slower decrease in NAA and increase in lactate, both detectable after 1 h. Exposure to NMDA for over 1 h or at higher concentrations caused further increases in lactate and decreases in NAA, with no further change in PCr or ATP. The L-isomer, NMLA, and the racemic mixture, NMDLA, caused similar changes in lactate and NAA, but both produced greater decreases in the energy state than NMDA, similar to those caused by prolonged exposure to glutamate. MK-801 prevented the changes in the energy state caused by NMDA, but not those caused by NMLA or by glutamate. The results are compared to previous studies on depolarization and discussed in terms of the role of the NMDA sub-type of glutamate receptor in the excitotoxic hypothesis of neuronal degeneration.
KEY WORDS: Depolarization; energy state; excitotoxicity; glutamate; intermediary metabolism; NMDA.
Abbreviations: MRS, Magnetic Resonance Spectroscopy; NAA, N-acetylaspartate; NMDA, N-methyl-D-aspartate; NMLA, N-methyl-L-aspartate; NMDLA, N-methyl-DL-aspartate; TSP, Trimethylsilylpropionate.
INTRODUCTION
The excitotoxic hypothesis, on the events underlying the neuronal death which occurs in stroke, epilepsy and many neurodegenerative disorders, is based on the proposal that the cellular damage results from excessive depolarization leading to release of the excitatory neurotransmitter glutamate, which cannot be re-uptaken due to the accompanying loss of energy. Activation of glutamate receptors, especially the N-methyl-D-aspartate (NMDA) subtype, is thought to lead to increased intracellular calcium which triggers a cascade of metabolic events resulting in cell death (1-4). However there is some evidence that the hypothesis does not explain adequately many aspects of metabolic and functional damage which occur in such disorders (5-7).
Earlier studies on the effects of low concentrations (10 mM) of NMDA (8-10) revealed that it causes relatively rapid decreases in phosphocreatine (PCr), ATP, NAA, glutamate and glutamine, with a slower increase in [Ca21]i. An unexpected observation was the slow release of intracellular zinc caused by NMDA, which appeared after the increase in [Ca21]i (10). Glutamate produced similar decreases in the energy state with more rapid changes in the two divalent cations (7,10). Pre-treatment with 10 mM-MK801, which blocks the NMDA sub-type of glutamate receptor, removed all of...