Inhibition of glutamate carboxypeptidase II (NAALADase) protects against dynorphin A-induced ischemic spinal cord injury in rats.
Glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), which is also known as N-acetylated-alpha-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.
Long
Joseph B
JB
Department of Polytrauma and Resuscitation Research, Division of Military Casualty Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. joseph.long@na.amedd.army.mil
Yourick
Debra L
DL
Slusher
Barbara S
BS
Robinson
Michael B
MB
Meyerhoff
James L
JL
D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000008:administration & dosage; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000134:cerebrospinal fluid; D007511:Ischemia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
C402107:2-(phosphonomethyl)pentanedioic acid; D009943:Organophosphorus Compounds; D018698:Glutamic Acid; D004399:Dynorphins; D043425:Glutamate Carboxypeptidase II