STRUCTURAL NEUROTOXICOLOGIC INVESTIGATION OF THE GLYCINE ANTAGONIST 5-NITRO-6,7-DICHLOROQUINOXALINEDIONE (ACEA-1021)

NMDA antagonists of glutamate ha ve psychotomimetic side effects and s tructural side effects which have been shown to be lethal to CNS neuro ns in the cingulate and retrosplenial cortex of rodents, yet these com pounds may reduce focal ischemic brain damage. This investigation used 38 Wistar rats to determine whether the structural toxicologic profil e of a newly developed halogenated quinoxalinedione derivative, a phar macologic antagonist of the glycine site on the NMDA receptor complex, is identical to that seen with MK-801. In the cingulate and retrosple nial cortex, examination of glutaraldehyde perfusion-fixed, plastic-em bedded tissue 4 to 6 hours after intravenous administration of 10 mg/k g of the glycine antagonist 5-nitro-6,7-dichloroquinoxalinedione (ACEA -1021), no changes were seen by light or electron microscopy. At a dos e of 30 mg/kg, neurons were seen containing 1 to 2 mu m granules in pe rikarya and axons. Vacuolated neurons, as described in NMDA-antagonist neurotoxicity, were exceedingly rare, comprising only 4 in the entire study. Electron microscopy of the granulated profiles showed intracyt oplasmic areas containing grouped mitochondria and lysosomes, located in neuronal perikarya, and rarely in myelinated axons. Neuronal necros is was evaluated in formaldehyde perfusion-fixed, paraffin-embedded ti ssue at one week survival, and was absent. MK-801 5 m/kg, in contrast, caused irreversible (necrotizing) neuronal changes. The results demon strate that this glycine antagonist is devoid of lethal neurotoxicity, but causes a reversible alteration in a small proportion of cingulate and retrosplenial cortical neurons. Since previous studies have shown anti-ischemic efficacy of this compound in focal, but not global ische mia, it appears that the therapeutic profile of this antagonist of the strychnine-insensitive glycine site is similar, but the toxicologic s tructural profile is different, from NMDA receptor antagonists. (C) 19 97 Inter Press, Inc.