1-Aminocyclopropanecarboxylic acid protects against dynorphin A-induced spinal injury.
Lumbar subarachnoid injection of dynorphin A causes an ischemia-induced neuronal degeneration and persistent hindlimb paralysis. The protective effects of a variety of competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists indicate that activation of the NMDA receptor complex is essential for dynorphin A-induced spinal cord injury. 1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity, partial agonist at strychnine-insensitive glycine receptors associated with the NMDA receptor complex. Pretreatment of rats with ACPC (100 and 200 mg/kg, i.p., 30 min prior to dynorphin A) significantly eliminated the persistent hindlimb motor deficits and neuropathological changes produced by 20 nmol of this peptide. The neuroprotective effects of ACPC (100 mg/kg, i.p.) were abolished by parenteral administration of glycine (800 mg/kg, 30 min prior to ACPC), consistent with other in vivo and in vitro studies indicating that the pharmacological actions of ACPC are effected through strychnine-insensitive glycine receptors. When given instead as six daily injections (200 mg/kg, i.p.) followed by an injection-free day, ACPC also significantly improved neurological recovery following dynorphin-A injection. These results support earlier indications that: (1) activation of the NMDA receptor complex plays a critical role in mediating dynorphin A-induced rat spinal cord injury; (2) ACPC provides an effective means of antagonizing excitotoxic phenomena; and (3) chronic administration of ACPC can elicit a persistent change in the NMDA receptor complex.
Long
J B
JB
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, D.C. 20307.
Skolnick
P
P
D000596:Amino Acids / Q000494:pharmacology*; D000598:Amino Acids, Cyclic; D000818:Animals; D004399:Dynorphins / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006614:Hindlimb / Q000502:physiology; D007267:Injections; D008297:Male; D010243:Paralysis / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013118:Spinal Cord Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013346:Subarachnoid Space
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D016194:Receptors, N-Methyl-D-Aspartate; C023863:1-aminocyclopropane-1-carboxylic acid; D004399:Dynorphins