THE CALMODULIN ANTAGONIST TRIFLUOPERAZINE IN TRANSIENT FOCAL BRAIN ISCHEMIA IN RATS - ANTIISCHEMIC EFFECT AND THERAPEUTIC WINDOW

Background and Purpose This study was performed to assess the efficacy and the therapeutic window for the calmodulin antagonist trifluoperaz ine in experiments involving transient middle cerebral artery (MCA) oc clusion. Methods 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 repea ted 24 hours after the first injection. Neurological scores and infarc t volumes were evaluated at 48 hours of reperfusion. The effect of tri fluoperazine on cortical blood flow was studied with continuous laser- Doppler flowmetry. Results 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; e ach n = 7). The percentage of infarct volume in the control rats was 3 4.8 +/- 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 penu mbra during and after ischemia. Conclusions The results demonstrate th at trifluoperazine markedly reduces infarct volume after 2 hours of MC A occlusion when given 5 minutes after the induction of ischemia. Howe ver, the therapeutic window for trifluoperazine seems narrow since the drug had no significant effect when given after 1 or 2 hours.