Neuroprotective effects of N-acetylaspartylglutamate in a neonatal rat model of hypoxia-ischemia.

Abstract

Neuroprotective effects of N-acetylaspartylglutamate (NAAG), the precursor of glutamate and a selective agonist at the Group II metabotropic glutamate (mGlu) receptor, against hypoxic-ischemic brain injury were examined in a neonatal rat model of cerebral hypoxia-ischemia. The neonatal hypoxia-ischemia procedure (unilateral carotid artery ligation followed by exposure to an 8% oxygen hypoxic condition for 1.5 h) was performed in 7-day-old rat pups. Following unilateral carotid artery ligation, NAAG (0.5 to 20 mg/kg, i.p.) was administered before or after the hypoxic exposure. Brain injury was examined 1-week later by weight reduction in the ipsilateral brain and by neuron density in the hippocampal CA1 area. In the saline-treated rat, neonatal hypoxia-ischemia resulted in severe brain injury as indicated by a 24% reduction in the ipsilateral brain weight. Low doses of NAAG (2-10 mg/kg, but not 0.5 mg/kg), administered before or even if 1 h after the hypoxic exposure, greatly reduced hypoxia-ischemia-induced brain injury (3.8-14.2% reduction in the ipsilateral brain weight). A high dose of NAAG (20 mg/kg) was ineffective. While L(+)-2-Amino-4-phosphonobutyric acid (L-AP4) and trans-[1S,3R]-1-Amino-cyclopentane-1, 3-dicarboxylic acid (t-ACPD) were unable to provide protection against hypoxic-ischemic brain injury, 2-(phosphonomethyl) pentanedioic acid (2-PMPA), an inhibitor of N-acetylated alpha-linked acidic dipeptidase (NAALADase), which hydrolyzes endogenous NAAG into N-acetyl-aspartate and glutamate, significantly reduced neonatal hypoxia-ischemia-induced brain injury. (alphaS)-alpha-Amino-alpha-[(1S, 2S)-2-carboxycyclopropyl]-9H-xanthine-9-propanoic acid (LY341495), a selective antagonist at the mGlu2/3 receptor, prevented the neuroprotective effect of NAAG. Neuron density data measured in the hippocampal CA1 area confirmed that ipsilateral brain weight reduction was a valid measure for hypoxic-ischemic brain injury. Neonatal hypoxia-ischemia stimulated an elevation of cyclic AMP (cAMP) concentration in the saline-treated rat brain. NAAG, L-AP4 and t-ACPD all significantly decreased hypoxia-ischemia-induced elevation of cAMP. LY341495 blocked the effect of NAAG, but not of L-AP4 or t-ACPD, on hypoxia-ischemia-stimulated cAMP elevation. The overall results suggest that the neuroprotective effect of NAAG is largely associated with activation of mGlu2/3 receptor.

• Authors: Zhengwei Cai, Shuying Lin, Philip G Rhodes
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 437 Issue 3 Pg. 139-45 (Feb 22 2002) ISSN: 0014-2999 [Print] Netherlands
• PMID: 11890901 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-(phosphonomethyl)pentanedioic acid
• 2-amino-4-phosphono-propinate
• Amino Acids
• Dipeptides
• Enzyme Inhibitors
• Excitatory Amino Acid Antagonists
• LY 341495
• Neuroprotective Agents
• Organophosphorus Compounds
• Propionates
• Xanthenes
• Cycloleucine
• 1-amino-1,3-dicarboxycyclopentane
• isospaglumic acid
• Cyclic AMP
• Carboxypeptidases
• Glutamate Carboxypeptidase II

Topics

• Amino Acids (pharmacology)
• Animals
• Animals, Newborn
• Brain (drug effects, metabolism, pathology)
• Carboxypeptidases (antagonists & inhibitors)
• Cyclic AMP (metabolism)
• Cycloleucine (analogs & derivatives, pharmacology)
• Dipeptides (pharmacology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• Glutamate Carboxypeptidase II
• Hippocampus (drug effects, metabolism, pathology)
• Hypoxia-Ischemia, Brain (metabolism, pathology, prevention & control)
• Neurons (drug effects, pathology)
• Neuroprotective Agents (pharmacology)
• Organophosphorus Compounds (pharmacology)
• Propionates (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Xanthenes (pharmacology)