TY - JOUR
T1 - Inhibition of glutamate carboxypeptidase II (NAALADase) protects against dynorphin A-induced ischemic spinal cord injury in rats
AU - Long, Joseph B.
AU - Yourick, Debra L.
AU - Slusher, Barbara S.
AU - Robinson, Michael B.
AU - Meyerhoff, James L.
N1 - Funding Information:
Funded by the U.S. Army Medical Research and Materiel Command. The research described in this report was conducted under a protocol approved by an Institutional Animal Care and Use Committee, in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals. All procedures were carried out in accordance with the Declaration of Helsinki and/or with the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense (para. 4-3), AR 360-5. The Mental Retardation and Developmental Disabilities Research Center (P30-HD26979) are gratefully acknowledged for the amino acid analyses.
PY - 2005/1/31
Y1 - 2005/1/31
N2 - Glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), which is also known as N-acetylated-α-linked acidic dipeptidase (NAALADase), hydrolyses the endogenous acidic dipeptide N-acetylaspartylglutamate (NAAG), yielding N-acetyl-aspartate and glutamate. Inhibition of this enzyme by 2-(phosphonomethyl) pentanedioic acid (2-PMPA) has been shown to protect against ischemic injury to the brain and hypoxic and metabolic injury to neuronal cells in culture, presumably by increasing and decreasing the extracellular concentrations of NAAG and glutamate, respectively. Since both NAAG and GCP II are found in especially high concentrations in the spinal cord, injuries to the spinal cord involving pathophysiological elevations in extracellular glutamate might be particularly responsive to GCP II inhibition. Lumbar subarachnoid injections of dynorphin A in rats cause ischemic spinal cord injury, elevated extracellular glutamate and a persistent hindlimb paralysis that is mediated through excitatory amino acid receptors. We therefore used this injury model to evaluate the protective effects of 2-PMPA. When coadministered with dynorphin A, 2-PMPA significantly attenuated the dynorphin A-induced elevations in cerebrospinal fluid glutamate levels and by 24 h postinjection caused significant dose-dependent improvements in motor scores that were associated with marked histopathological improvements. These results indicate that 2-PMPA provides effective protection against excitotoxic spinal cord injury.
AB - Glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), which is also known as N-acetylated-α-linked acidic dipeptidase (NAALADase), hydrolyses the endogenous acidic dipeptide N-acetylaspartylglutamate (NAAG), yielding N-acetyl-aspartate and glutamate. Inhibition of this enzyme by 2-(phosphonomethyl) pentanedioic acid (2-PMPA) has been shown to protect against ischemic injury to the brain and hypoxic and metabolic injury to neuronal cells in culture, presumably by increasing and decreasing the extracellular concentrations of NAAG and glutamate, respectively. Since both NAAG and GCP II are found in especially high concentrations in the spinal cord, injuries to the spinal cord involving pathophysiological elevations in extracellular glutamate might be particularly responsive to GCP II inhibition. Lumbar subarachnoid injections of dynorphin A in rats cause ischemic spinal cord injury, elevated extracellular glutamate and a persistent hindlimb paralysis that is mediated through excitatory amino acid receptors. We therefore used this injury model to evaluate the protective effects of 2-PMPA. When coadministered with dynorphin A, 2-PMPA significantly attenuated the dynorphin A-induced elevations in cerebrospinal fluid glutamate levels and by 24 h postinjection caused significant dose-dependent improvements in motor scores that were associated with marked histopathological improvements. These results indicate that 2-PMPA provides effective protection against excitotoxic spinal cord injury.
KW - (N-acetylaspartylglutamate)
KW - (N-acetylated-α-linked acidic dipeptidase)
KW - (N-methyl-d-aspartate)
KW - (glutamate carboxypeptidase II)
KW - Dynorphin A
KW - GCP II
KW - NAAG
KW - NAALADase
KW - NMDA
KW - Neuroprotection
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UR - http://www.scopus.com/inward/citedby.url?scp=12844281342&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2004.12.008
DO - 10.1016/j.ejphar.2004.12.008
M3 - Article
C2 - 15680261
AN - SCOPUS:12844281342
VL - 508
SP - 115
EP - 122
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 1-3
ER -