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 alpha-amino-3-hydroxy-5-methylisoazole-4-propionic acid/kainate or AMPA/kainate subtype, may predominate in the adult brain. In this experiment, a selective AMPA antagonist, NBQX, was used in a canine survival model of hypothermic circulatory arrest. Twelve male dogs (20 to 25 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of hypothermic circulatory arrest at 18 degrees C, and rewarmed on cardiopulmonary bypass. All were mechanically ventilated and monitored for 20 hours before extubation and survived for 3 days. Six dogs received NBQX beginning 2 hours after arrest (3 mg/kg for 3 hours then 1.5 mg/kg for 2 hours). Control dogs received vehicle only. Neurologic recovery was assessed every 12 hours using a species-specific behavior scale that yielded a neurodeficit score ranging from 0 (normal) to 500 (brain dead). After sacrifice at 72 hours, brains were examined by receptor autoradiography and histologically for patterns of selective neuronal necrosis and scored blindly from 0 (normal) to 100 (severe injury). Dogs given NBQX had better neurologic function compared with controls (neurodeficit score, 58.6 +/- 15 versus 204 +/- 30; p < 0.004) and had less neuronal injury (18.2 +/- 3 versus 52.5 +/- 6; p < 0.004). Densitometric receptor autoradiography revealed preservation of neuronal NMDA receptor expression only in dogs given NBQX. These results suggest that antagonism of the non-NMDA glutamate receptor AMPA may be neuroprotective in adults after hypothermic circulatory arrest.
Redmond
J M
JM
Division of Cardiac Surgery, Johns Hopkins Medical Institution, Baltimore, Maryland.
Zehr
K J
KJ
Blue
M E
ME
Lange
M S
MS
Gillinov
A M
AM
Troncoso
J C
JC
Cameron
D E
DE
Johnston
M V
MV
Baumgartner
W A
WA
D000818:Animals; D001345:Autoradiography; D001927:Brain Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002315:Cardiopulmonary Bypass; D004285:Dogs; D004569:Electroencephalography; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D007036:Hypothermia, Induced / Q000009:adverse effects; D008297:Male; D009336:Necrosis; D009474:Neurons / Q000473:pathology; D011182:Postoperative Care; D011810:Quinoxalines / Q000627:therapeutic use*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017694:Rewarming; D015996:Survival Rate; D013997:Time Factors
D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline