N-Acetylated α-Linked Acidic Dipeptidase Converts N-Acetylaspartylglutamate from a Neuroprotectant to a Neurotoxin
We previously reported that inhibition of the brain enzyme N- acetylated α-linked acidic dipeptidase (NAALADase; glutamate carboxypeptidase II) robustly protects cortical neurons from ischemic injury. Since NAALADase hydrolyzes N -acetylaspartylglutamate (NAAG) to glutamate we hypothesized that inh...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 295; no. 1; p. 16 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Pharmacology and Experimental Therapeutics
01.10.2000
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Online Access | Get full text |
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Summary: | We previously reported that inhibition of the brain enzyme N- acetylated α-linked acidic dipeptidase (NAALADase; glutamate carboxypeptidase II) robustly protects cortical neurons from
ischemic injury. Since NAALADase hydrolyzes N -acetylaspartylglutamate (NAAG) to glutamate we hypothesized that inhibiting NAALADase would both decrease glutamate and increase
NAAG. Increasing NAAG is potentially important because NAAG is a metabotropic glutamate receptor agonist and an N -methyl- d -aspartate (NMDA) partial antagonist, both of which have previously been shown to be neuroprotective. To understand the likely
effects of endogenous NAAG in the central nervous system, we have now investigated the activity of NAAG in primary cortical
cultures while manipulating NAALADase activity. Under hydrolyzing conditions, when NAALADase was active, NAAG had toxic effects
that were blocked by NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists and
by NAALADase inhibition. NAAG's toxic effects were presumably due to the liberation of glutamate. Under nonhydrolyzing conditions,
when NAALADase was inhibited, NAAG demonstrated neuroprotective effects against both NMDA toxicity and metabolic inhibition.
In the case of NMDA-induced toxicity, NAAG provided neuroprotection through its partial antagonist activity at the NMDA receptor.
In the case of metabolic inhibition, NAAG had an additional neuroprotective effect mediated through its agonist properties
at the type II metabotropic glutamate receptor. These results indicate that NAAG might play an important role in the central
nervous system, under certain pathological conditions, as a neurotoxin or as a neuroprotectant, depending on the activity
of NAALADase. |
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ISSN: | 0022-3565 1521-0103 |