N-acetylaspartylglutamate and β-NAAG protect against injury induced by NMDA and hypoxia in primary spinal cord cultures

• Published in: Brain research Vol. 991; no. 1; pp. 56 - 64
• Main Authors: Yourick, Debra L, Koenig, Michael L, Durden, Anna V, Long, Joseph B
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 21-11-2003; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Biological and medical sciences; Calcium; Calcium - metabolism; Cell Hypoxia - physiology; Cell Survival - drug effects; Cells, Cultured; Dipeptides - pharmacology; Glutamate; Medical sciences; mGluR; N-Acetyl-β-aspartylglutamate; N-Acetylaspartylglutamate; N-Methylaspartate - pharmacology; NAAG peptidase activity, glutamate carboxypeptidase II or NAALADase; Neurons - drug effects; Neurons - pathology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; NMDA; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Spinal Cord - drug effects; Spinal Cord - pathology; Neuroprotection; NAAG peptidase activity, glutamate carboxypeptidase II or NAALADase; Calcium; N-Acetylaspartylglutamate; NMDA; Glutamate; Neurotransmitters, modulators, transporters, and receptors; N-Acetyl-β-aspartylglutamate; mGluR; Oxygen; Spinal cord; Rat; Toxicity; glutamate carboxypeptidase II or NAALADase; Glutamate; Neuroprotection; Calcium; NMDA; mGluR; Rodentia; Central nervous system; Enzyme inhibitor; Environmental factor; Glutamate receptor; Neuroprotective agent; In vitro; Vertebrata; Mammalia; N-Acetylaspartylglutamate; N-Acetyl-β-aspartylglulamate; NAAG peptidase activity; Excitotoxicity; Dipeptides; Hypoxia; NMDA receptor
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(03)03533-9

The acidic dipeptide
N-acetylaspartylglutamate (NAAG) is the most prevalent peptide in the central nervous system. NAAG is a low potency agonist at the NMDA receptor, and hydrolysis of NAAG yields the more potent excitatory amino acid neurotransmitter glutamate. β-NAAG is a competitive inhibitor of the NAAG hydrolyzing enzyme
N-acetylated α-linked acidic dipeptidase (NAAG peptidase activity) or glutamate carboxypeptidase II, and may also act as a NAAG-mimetic at some of the sites of NAAG pharmacological activity. Since NAAG has been shown to have neuroprotective characteristics in a number of experimental preparations, it is the purpose of the present study to specifically evaluate the possible efficacy of NAAG and β-NAAG against NMDA- and hypoxia-induced injury to spinal cord mixed neuronal and glial cell cultures. NAAG (500–1000 μM) protected against NMDA- or hypoxia-induced injuries to spinal cord cultures, and the nonhydrolyzable analog β-NAAG (250–1000 μM) completely eliminated the loss of viability caused by either insult. Both peptides also attenuated NMDA-induced increases in intraneuronal Ca
2+. Nonspecific mGluR antagonists, pertussis toxin, a stable cAMP analog, and manipulation of NAAG peptidase activity did not by themselves alter cell damage and did not influence the neuroprotective effects of NAAG. NAAG was not protective against kainate- or AMPA-induced cellular injury, while β-NAAG was partially neuroprotective against both insults. At 2 mM, NAAG and β-NAAG reduced neuronal survival and increased intraneuronal Ca
2+; these effects were only marginally attenuated by dizocilpine and APV. The results indicate that NAAG and β-NAAG protect against excitotoxic and hypoxic injury to spinal cord neurons, and do so predominantly by interactions with NMDA and not mGluR receptors.