1-AMINOCYCLOPROPANECARBOXYLIC ACID PROTECTS AGAINST DYNORPHIN A-INDUCED SPINAL-INJURY

Lumbar subarachnoid injection of dynorphin A causes an ischemia-induce d neuronal degeneration and persistent hindlimb paralysis. The protect ive 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 cor d injury. 1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity , partial agonist at strychnine-insensitive glycine receptors associat ed with the NMDA receptor complex. Pretreatment of rats with ACPC (100 and 200 mg/kg, i.p., 30 min prior to dynorphin A) significantly elimi nated the persistent hindlimb motor deficits and neuropathological cha nges 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.) followe d by an injection-free day, ACPC also significantly improved neurologi cal recovery following dynorphin-A injection. These results support ea rlier indications that: (1) activation of the NMDA receptor complex pl ays a critical role in mediating dynorphin A-induced rat spinal cord i njury; (2) ACPC provides an effective means of antagonizing excitotoxi c phenomena; and (3) chronic administration of ACPC can elicit a persi stent change in the NMDA receptor complex.