Effect of CP101,606, a novel NR2B subunit antagonist of the N-methyl-D-aspartate receptor, on the volume of ischemic brain damage off cytotoxic brain edema after middle cerebral artery occlusion in the feline brain.
OBJECTIVE
The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke.


METHODS
Seventeen adult cats were allocated to control (n = 7) and CP101,606-treated groups (n = 10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)-stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage.


RESULTS
The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P < .001).


CONCLUSIONS
CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.
Di
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Division of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University 23298-0631, USA.
Bullock
R
R
Watson
J
J
Fatouros
P
P
Chenard
B
B
White
F
F
Corwin
F
F
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology*; D001921:Brain / Q000473:pathology; D001929:Brain Edema / Q000175:diagnosis / Q000473:pathology*; D002545:Brain Ischemia / Q000175:diagnosis / Q000473:pathology*; D002415:Cats; D002536:Cerebral Arteries; D002544:Cerebral Infarction / Q000473:pathology; D015314:Dialysis Solutions / Q000737:chemistry; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007773:Lactates / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013194:Staining and Labeling; D013778:Tetrazolium Salts
D015314:Dialysis Solutions; D018691:Excitatory Amino Acid Antagonists; D007773:Lactates; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; C095106:traxoprodil mesylate