AMPA GLUTAMATE-RECEPTOR ANTAGONISM REDUCES NEUROLOGIC INJURY AFTER HYPOTHERMIC CIRCULATORY ARREST

Pharmacologic inhibition of the N-methyl-D-aspartate (NMDA) glutamate receptor can reduce the neurologic injury associated with hypothermic circulatory arrest; however, other receptor subtypes, such as the alph a-amino-3-hydroxy-5-methylisoazole-4-propionic acid/kainate or AMPA/ka inate subtype, may predominate in the adult brain. In this experiment, a selective AMPA antagonist, NBQX, was used in a canine survival mode l of hypothermic circulatory arrest. Twelve male dogs (20 to 25 kg) we re placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of hypothermic circulatory arrest at 18 degrees C, and rewarmed on ca rdiopulmonary bypass. All were mechanically ventilated and monitored f or 20 hours before extubation and survived far 3 days. Six dogs receiv ed NBQX beginning 2 hours after arrest (3 mg/kg for 3 hours then 1.5 m g/kg for 2 hours). Control dogs received vehicle only. Neurologic reco very was assessed every 12 hours using a species-specific behavior sca le that yielded a neurodeficit score ranging from 0 (normal) to 500 (b rain dead). After sacrifice at 72 hours, brains were examined by recep tor autoradiography and histologically for patterns of selective neuro nal necrosis and scored blindly from 0 (normal) to 100 (severe injury) . Dogs given NBQX had better neurologic function compared with control s (neurodeficit score, 58.6 +/- 15 versus 204 +/- 30; p < 0.004) and h ad less neuronal injury (18.2 +/- 3 versus 52.5 +/- 6; p < 0.004). Den sitometric receptor autoradiography revealed preservation of neuronal NMDA receptor expression only in dogs given NBQX. These results sugges t that antagonism of the non-NMDA glutamate receptor AMPA may be neuro protective in adults after hypothermic circulatory arrest.