Competitive N-methyl-D-aspartate receptor blockade reduces brain injury following transient focal ischemia in cats.
OBJECTIVE
We tested the hypothesis that administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist NPC 17742 (2R,4R,5S-[2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid]) during transient focal ischemia affects early postischemic brain injury.


METHODS
Halothane-anesthetized cats underwent 1 hour of left middle cerebral artery occlusion plus 4 hours of reperfusion. Control cats received saline (n = 7). Experimental cats were treated with NPC 17742 at a dose of 5 mg/kg IV from 45 minutes of ischemia to 15 minutes of reperfusion and 2.5 mg/kg per hour for 4 hours of reperfusion (NPC-5; n = 7) or 50 mg/kg from 45 minutes of ischemia to 15 minutes of reperfusion and 25 mg/kg per hour for 4 hours of reperfusion (NPC-50; n = 5).


RESULTS
Microsphere-determined blood flow to the ipsilateral inferior temporal cortex and caudate nucleus decreased to the same extent during ischemia and recovered to the same extent during reperfusion in the three groups. Triphenyltetrazolium-determined injury volume of ipsilateral cerebral hemisphere (saline, 24 +/- 8%; NPC-5, 4 +/- 2%; NPC-50, 5 +/- 2% of hemisphere; mean +/- SE) and caudate nucleus (saline, 72 +/- 6%; NPC-5, 37 +/- 10%; NPC-50, 26 +/- 4%) was less in cats treated with both doses of drug compared with cats treated with saline. Recovery of somatosensory evoked potential amplitude was incomplete and similar in all groups (saline, 36 +/- 14%; NPC-5, 58 +/- 8%; NPC-50, 51 +/- 15% of baseline).


CONCLUSIONS
These data indicate that activation of NMDA receptors plays an important role in the mechanism of acute injury in both cortex and caudate after 1 hour of transient focal ischemia in the cat. Because NPC 17742 afforded protection when administered at the end of ischemia and during reperfusion, NMDA receptor activation during reperfusion may contribute to the progression of injury in ischemic border regions.
Nishikawa
T
T
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Kirsch
J R
JR
Koehler
R C
RC
Miyabe
M
M
Traystman
R J
RJ
D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000473:pathology*; D002415:Cats; D002560:Cerebrovascular Circulation; D004334:Drug Administration Schedule; D005073:Evoked Potentials, Somatosensory; D005260:Female; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology; D008863:Microspheres; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013194:Staining and Labeling; D013778:Tetrazolium Salts; D013997:Time Factors
D000596:Amino Acids; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; C060212:NPC 12626; C009591:triphenyltetrazolium