A SIMPLE AND REPRODUCIBLE CEREBRAL THROMBOSIS MODEL IN RATS INDUCED BY A PHOTOCHEMICAL-REACTION AND THE EFFECT OF A PLASMINOGEN PLASMINOGEN-ACTIVATOR CHIMERA IN THIS MODEL

In this study a new model of cerebral ischemia, based on a middle cerebral artery (MCA) thrombosis in rats is described. Furthermore, the effect of the novel plasminogen activator (SUN9216), a plasminogen-plasminogen activator chimera, comprising the fibrin kringle 1 domain of a plasminogen, and the two kringles, and the serine protease domains of wild-type tissue plasminogen activator (t-PA), including a modification of the mannose glycosylation site on the kringle 1 of t-PA (PK1de1FE1X), was studied in this model. In the newly described model of thrombotic cerebral ischemia, an occlusive thrombus occurred usually within 8 min in the MCA as a consequence of an endothelial injury subsequent to a photochemical reaction between a systemically administered photosensitive dye (rose bengal) and a transillumination of the MCA with a high-intensity green light with a wavelength of 540 nm. The study was quantitated by means of pathological examination of the MCA and the brain. A platelet-rich thrombus was observed in the MCA using electron microscopical analysis based on ion beam bombardment. At 24 hr after induction of the thrombus, the brain was removed from 13 control animals, nine coronal sections were stained from each brain with triphenyltetrazoliumchloride (TTC), and the ischemic area was quantitated. A constant area of infarction was observed in the cortex and the lateral part of the basal ganglia. In a second group (n = 8), at 1 or 8 weeks after induction of the thrombosis in the MCA, the coronal sections were stained with hematoxylin and eosin. Glial cells were present in the infarcted area 24 hr after occlusion of the MCA, and after 8 weeks the infarcted area transformed into a cavity. A single intravenous bolus injection of the plasminogen-plasminogen activator chimera (SUN9216) 30 min after thrombus formation, significantly decreased the ischemic area as compared to the untreated animals 24 hr after induction of the thrombus. Thus, the described model of the photochemically induced thrombosis in the middle cerebral artery of the rat is a simple and reproducible in vivo model that may be useful for the investigation of cerebral infarction as well as the treatment of this disease.