Neuroprotective effect of NMDA receptor glycine recognition site antagonism persists when brain temperature is controlled.
Several lines of inquiry have indicated that glycine plays an important role in both glutamatergic neurotransmission and pathophysiology of cerebral ischemia. However, subacute outcome trials demonstrating the efficacy of glycine antagonists as neuroprotectants have not been performed with rigorous control of brain temperature. In this study, we investigated the effect of N-methyl-D-aspartate (NMDA) receptor glycine recognition site antagonism in a temperature-controlled rodent model of transient focal ischemia. Male Wistar rats underwent 75 min of intraluminal middle cerebral artery occlusion (MCAO). During MCAO and the first 24 h of reperfusion, rats (n = 10) were administered e55-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021) i.v. as a bolus infusion of 5 mg/kg followed by 3.5 mg/kg/h (Low-Dose) or 10 mg/kg followed by 7 mg/kg/ h (High-Dose) for 24 h. Cortical temperature was controlled at 38.0 +/- 0.1 degrees C during MCAO and the first 6 h of reperfusion. A 7-day recovery interval was allowed. Mean total infarct volume was reduced by approximately 40% in both high- and low-dose groups (p < 0.01). The preponderance of infarct reduction occurred in the cortex (p < 0.01). Neurologic function correlated with the size of cerebral infarct (p = 0.001). Neurologic grade was similarly improved by treatment with either dose (p = 0.01). These results demonstrate that neuroprotection achieved by antagonism of the glycine recognition site persists when brain temperature is controlled, indicating a potent mechanism of action other than attenuating a hyperthermic response to ischemia.
Takaoka
S
S
Department of Anesthesiology and Resuscitation, Yamagata University, Japan.
Bart
R D
RD
Pearlstein
R
R
Brinkhous
A
A
Warner
D S
DS
D000818:Animals; D001665:Binding Sites; D001925:Brain Damage, Chronic / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005334:Fever / Q000517:prevention & control; D005998:Glycine / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013696:Temperature
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C092062:licostinel; D005998:Glycine