N-acetylaspartylglutamate protects against transient focal cerebral ischemia in rats.
The inhibition of N-acetylated alpha-linked acidic dipeptidase (NAALADase: glutamate carboxypeptidase II) has been previously shown to protect against ischemic injury presumably through mechanisms of decreasing glutamate and increasing N-acetylaspartylglutamate (NAAG). Preventing excessive glutamate release is known to be neuroprotective. However, the role of increased NAAG is not clear. We used a middle cerebral artery occlusion model in rats to investigate the neuroprotective effect of NAAG via its action as a metabotropic glutamate (mGlu) receptor agonist. Rats received intracerebral injections of NAAG (1, 2, or 4 micromol), or a co-injection of NAAG (2 micromol) and the non-selective mGlu receptor antagonist, (R,S)-alpha-methyl-4-carboxyphenylglycine, (MCPG, 2 micromol). Immediately after the treatment, the animals received 2 h of middle cerebral artery occlusion followed by 22 h of reperfusion. Treatment with 1 or 2 micromol of NAAG significantly reduced total infarct volume. Treatment with MCPG partially attenuated the neuroprotective effect of NAAG, indicating that the protective effect of NAAG against ischemic injury may be in part mediated via activation of mGlu receptors.
Lu
X M
XM
Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA.
Tang
Z
Z
Liu
W
W
Lin
Q
Q
Slusher
B S
BS
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001565:Benzoates; D004151:Dipeptides; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; C079694:alpha-methyl-4-carboxyphenylglycine; C027172:isospaglumic acid; D005998:Glycine