Flunarizine reduces cerebral infarct size after photochemically induced thrombosis in spontaneously hypertensive rats

Abstract

The cerebroprotective effect of flunarizine was studied in a minimally invasive model of photochemically induced cerebral infarction in spontaneously hypertensive rats. Intravenous administration of the photosensitizing dye rose bengal and intense focal illumination of the brain produced a deep cortical infarction that resulted from singlet oxygen-induced peroxidative injury to the endothelial membrane, subsequent platelet adhesion, and eventual thrombus formation. The infarct size was calculated from area measurements on consecutive histologic sections prepared from the brain cortex 4 hours after the onset of the insult. Oral treatment with 40 mg/kg flunarizine 3 hours before photoexcitation resulted in a significant reduction of the median infarct size from 11.75 mm3 in the untreated group to 6.40 mm3 in the treated group (a = 13, p< 0.001). At this dose, flunarizine had no effect on systemic blood pressure. In a separate experiment the area of thrombotic obstruction was quantified 30 minutes after the onset of light exposure. Flunarizine did not significantly reduce early thrombus formation (2.28 mm3 in the untreated and 1.78 mm3 in the treated group) (n = 12, p = 0.2). The infarcted area at 4 hours was considerably larger than the initial thrombotic area. Protection with flunarizine against development of cortical infarction has been unequivocally shown. Although some effect may already be present at the early stage of lesion formation, the major protective action admittedly occurred in the later post insult period when the lesion was expanding. The observed beneficial effects may be attributed to preservation of the integrity of endothelial cell membranes (reduction of platelet adhesion and vasogenic edema formation), of neuronal cell membranes (inhibition of toxic Ca2+ overload), and of glial cell membranes (prevention of cytotoxic edema formation). The results indicate that flunarizine may be of clinical use for the suppression of thrombotic stroke. © 1987 American Heart Association, Inc.