EFFECT OF MCI-9038, A SELECTIVE THROMBIN INHIBITOR, ON CEREBRAL MICROCIRCULATION AFTER CEREBRAL ISCHEMIA IN RATS

MCI-9038', a synthetic thrombin inhibitor No. 805, has been shown to be effective for various thrombotic diseases including cerebral thrombosis in acute stage. In this report, we studied the effect of MCI-9038 on disorders of cerebral microcirculation in rats generated by the method of Pulsinelli et al. One day after both vertebral arteries were electrocauterized with electrocautery needle through the alar foramina, bilateral carotid arteries were occluded with Vari-angle aneurythm clips to induce hemispheric ischemia, which was confirmed by electroencepharograms becoming isoelectric. Thirty min. after bilateral carotid artery occlusion, clips were removed to restore carotid blood flow and 5 min. later India ink was infused to detect no-perfusion region. The brain was removed and noperfusion area (NPA) was measured for 10 colonal sections of the brain. While NPA in the control group was 14.6 ± 0.7 % of the total area of 10 colonal sections, MCI-9038 significantly reduced NPA to 5.8 ± 2.1 % at 5 mg/kg i.p. and 6.3 ± 1.3 % at 10 mg/kg i.p. Heparin at 50 and 100 u/kg i.v. and tissue culture urokinase (TCUK) at 48,000 and 96,000 u/kg i.v. did not reduce NPA. Electronmicroscopical observation revealed the platelet aggregates occluding the micro vessels in the region of noperfusion, suggesting that disorders of cerebral microcirculation in this model resulted from the obstruction of blood flow by micro platelet aggregates. MCI-9038 is considered to improve the cerebral microcirculation by the inhibition of the formation of platelet aggregates. Since MCI-9038 does not inhibit platelet aggregation induced by collagen, ADP or arachidonic acid but by thrombin potently, thrombin is considered to take an important role to form the micro platelet aggregates in this model. The difference in the effectiveness between MCI-9038 and heparin is discussed.