MRI study on delayed ancrod therapy of focal cerebral ischaemia in rats

The therapeutic window for efficient post-treatment of focal cerebral ischaemia with the fibrinogen lowering agent ancrod was studied by magnetic resonance imaging (MRI) in spontaneously hypertensive rats (SHR). Ancrod or vehicle solution (0.9% NaCl) were i.v. infused (0.12 IU/kg per min) via implanted mini pumps starting 0.5, 1.5, 3 or 6 h after permanent proximal middle cerebral artery occlusion and lasting until brain mapping by multislice T2-weighted magnetic resonance imaging in vivo 24 h after middle cerebral artery occlusion. Plasma fibrinogen concentrations were measured before middle cerebral artery occlusion, before pump implantation and after magnetic resonance imaging. Total brain lesion volumes as determined by magnetic resonance imaging 24 h after middle cerebral artery occlusion were 131 +/- 36 (188 +/- 28)*, 151 +/- 39 (194 +/- 39)*, 147 +/- 44 (207 +/- 33)* and 209 +/- 60 (214 +/- 42) mm3 in rats with 0.5, 1.5, 3 and 6 h, respectively, delay of ancrod treatment (means +/- S.D., 8-11 animals/group, corresponding control groups in parentheses, *P < 0.05). Continuous i.v. ancrod infusions reduced plasma fibrinogen levels significantly (P < 0.05) in all ancrod-treated groups as compared to vehicle-treated controls until the end of the experiments 24 h after middle cerebral artery occlusion. In conclusion, significant cerebroprotection was achieved even when the onset of ancrod therapy for lowering of the plasma fibrinogen level was delayed for up to 3 h. To the best of our knowledge no drug efficacy has been reported so far with a therapeutic window of 3 h after permanent middle cerebral artery occlusion in spontaneously hypertensive rats suggesting that ancrod may provide an efficient therapy of acute human stroke.