The calmodulin antagonist trifluoperazine in transient focal brain ischemia in rats. Anti-ischemic effect and therapeutic window.

Abstract

This study was performed to assess the efficacy and the therapeutic window for the calmodulin antagonist trifluoperazine in experiments involving transient middle cerebral artery (MCA) occlusion. Male Wistar rats were subjected to transient (2 hours) MCA occlusion by an intraluminal filament technique. Trifluoperazine (5.0 mg.kg-1) was injected intraperitoneally 5 minutes, 1 hour, or 2 hours after the induction of ischemia. Drug administration was repeated 24 hours after the first injection. Neurological scores and infarct volumes were evaluated at 48 hours of reperfusion. The effect of trifluoperazine on cortical blood flow was studied with continuous laser-Doppler flowmetry. The median value of neurological scores in the control rats (n = 7) was 3, while those in the treated groups were 1 (5-minute group; n = 7, P < .05) and 2 (1-hour and 2-hour groups; each n = 7). The percentage of infarct volume in the control rats was 34.8 +/- 4.9% (mean +/- SD), while those in the treated groups were 11.3 +/- 12.3% (5-minute group; P < .01), 24.8 +/- 15.1% (1-hour group), and 28.8 +/- 8.3% (2-hour group). Trifluoperazine, given at 5 minutes after ischemia, had no influence on blood flow in the neocortical penumbra during and after ischemia. The results demonstrate that trifluoperazine markedly reduces infarct volume after 2 hours of MCA occlusion when given 5 minutes after the induction of ischemia. However, the therapeutic window for trifluoperazine seems narrow since the drug had no significant effect when given after 1 or 2 hours.