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 mm 3 in the untreated group to 6.40 mm 3 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 mm 3 in the untreated and 1.78 mm 3 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 postinsult 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 Ca 2+ 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.

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

“…17 In these experiments, upon administration of Rose Bengal, oxygen singlet species are generated after illumination of brain cortex, causing peroxydation of endothelial cell membranes, occlusive platelet aggregation, microthrombi formation and focal cerebral ischemia. 55 Following the protocol described in the Methods section, we injected i.p. five times saline, ITH12246, or melatonin, both dissolved in saline; with the first injection being 20 min before ischemia (day 0), following two doses per day (day 1 and 2 postischemia).…”

Photothrombotic Ischemia: A Minimally Invasive and Reproducible Photochemical Cortical Lesion Model for Mouse Stroke Studies

“…Although laser-mediated excitation was still used recently5, it can be replaced by cold light lamp that also ensure dye excitation 10,15 . Cold light optic fibers are easier to manipulate and less expensive than laser sources.…”

Rodent models of cerebral ischemia.

“…120 - 121 In other applications, this model has been used to study calcium channel blocker therapy in stroke 122 and has yielded unexpected evidence of a slight protective effect of hyperglycemia in the setting of microvascular occlusion. 123 A photochemical technique has also been used to generate a useful model of graded spinal cord infarction.…”