Human recombinant tissue-plasminogen activator (alteplase): why not use the 'human' dose for stroke studies in rats?

Abstract

Since a pioneer work that has shown in vitro that the rat's fibrinolytic system is 10-fold less sensitive to recombinant tissue-plasminogen activator (rtPA) than the human system, most preclinical studies are performed with 10 instead of 0.9 mg/kg rtPA (the clinical dose in stroke patients). In this study, we compared the effects of these doses on mean time to reperfusion, reperfusion slope, brain infarct volume and edema in a rat model of thrombo-embolic stroke. Our data provide evidence that the dose of 0.9 mg/kg rtPA is as appropriate as that of 10 mg/kg for preclinical stroke studies in rodents.

Figure 1

Time course (A) and cumulated (B) effects of the recombinant tissue-plasminogen activator (rtPA) at 0.9 and 10 mg/kg on cerebral blood flow reperfusion (CBF), in rats subjected to middle cerebral artery occlusion produced by administration of an autologous blood clot. (A) was obtained by averaging all CBF–time curves for a group. Although error bars were omitted for clarity of presentation in (A), variability for each group can be viewed in (B). (C, D) Rats treated with 0.9 or 10 mg/kg rtPA, respectively, showed significantly different mean time to reperfusion of 39.6±3.3 and 25.2±3.1 mins (C), but exhibited similar reperfusion slopes (0.9 mg/kg rtPA: y=2.2643+14.786, r²=0.9083, n=7, P<0.001; 10 mg/kg rtPA: y=2.5x+34.714, r²=0.9811, n=7, P<0.001) as calculated from the time reperfusion actually started (D). Taken together, these data indicate that differences in reperfusion between 0.9 and 10 mg/kg rtPA mainly resulted from a slower effect of 0.9 mg/kg rtPA at starting reperfusion rather than from differences in the kinetics and the dynamics of reperfusion by itself. (E, F) Rats treated with 10 mg/kg rtPA showed a trend toward smaller brain infarction volume (95.1±41.9 vs 165±11 mm³) (E) and tissue edema (3.5±2.7% vs 11.6±0.4%) (F) than rats treated with 0.9 mg/kg rtPA (P<0.10). ^#P<0.05 vs sham-treated rats; ^*P<0.05 vs rats treated with 10 mg/kg rtPA. Data are mean±s.e.m.