Comparative analysis of brain protection by N-methyl-D-aspartate receptor antagonists after transient focal ischemia in cats.

OBJECTIVE

We tested the hypothesis that the administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) (NPC 17742) or cis-4-(phosphonomethyl) piperidine-2-carboxylic acid (CGS 19755) or the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), at the appropriate doses, would all have efficacy in decreasing early postischemic brain injury in a feline model of transient focal ischemia.

DESIGN

Prospective, randomized, controlled animal trial.

SETTING

University research laboratory.

SUBJECTS

Forty mixed-breed cats.

INTERVENTIONS

Halothane-anesthetized cats underwent 90 mins of left middle cerebral artery occlusion plus 4 hrs of reperfusion. At 75 mins of ischemia, control cats received intravenous saline (n = 10). Experimental cats (n = 10 in each group) were treated with NPC 17742 (5 mg/kg bolus and 2.5 mg/kg/hr throughout reperfusion), MK-801 (5 mg/kg intravenous bolus), or CGS 19755 (40 mg/kg intravenous bolus) in a randomized fashion.

MEASUREMENTS AND MAIN 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 early reperfusion, in the four groups. Triphenyltetrazolium-determined injury volume of the ipsilateral caudate nucleus in cats treated with NPC 17742 (105 +/- 25 [SEM] mm3), MK-801 (97 +/- 22 mm3), and CGS 19755 (97 +/- 13 mm3) was less than in control cats (198 +/- 21 mm3). Hemisphere injury volumes with NPC 17742 (1209 +/- 405 mm3) and MK-801 (1338 +/- 395 mm3) were less than that value in controls (2193 +/- 372 mm3), whereas injury volume with CGS 19755 (1553 +/- 519 mm3) treatment did not attain significance (p < .09).

CONCLUSIONS

NMDA receptor activation during reperfusion may contribute to the progression of injury in ischemic border regions after 90 mins of transient focal ischemia in the cat. At the doses chosen, there appear to be no major differences in therapeutic efficacy for competitive and noncompetitive NMDA receptor antagonists.