F Cornelissen — Page 2

PubMedDate not supplied

Sabeluzole stabilizes the neuronal cytoskeleton.

There is growing evidence that cytoskeletal instability of neuronal cells is an important step towards tangle formation and subsequent functional disconnection in the AD brain. Sabeluzole, a new drug in clinical trials for Alzheimer's disease (AD), has been shown to slow down the clinical progression of the disease. In a search for the mechanism of action of this compound, the effect of sabeluzole on the neuronal cytoskeleton was investigated. Previous studies have shown that in human TR14 neuroblastoma cells and in rat hippocampal neurons a hyperstimulating medium of kinase activators leads to induction of aberrant tau phosphorylation followed by neurotoxicity. This report documents the attenuation of this neurotoxicity by sabeluzole. By selective permeabilization procedures and quantitative immunocytochemistry we show that the compound is found to preferentially increase the fraction of polymerized tubulin. Evidence is presented that the compound differentially modulates a nocodazole-induced depolymerization in contrast to a cold-induced depolymerization. In the mouse, N4 neuroblastoma cells sabeluzole decreases the spontaneous retraction frequency of neurites and lowers the lateral mobility of the cells. We, therefore, propose that sabeluzole exerts its neuroprotective effect by a stabilization of the neuronal cytoskeleton and that this mechanism provides a completely new approach for treatment in Alzheimer's disease.

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PubMedDate not supplied

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

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 (n = 13, p less than 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 postinsult period when the lesion was expanding.(ABSTRACT TRUNCATED AT 250 WORDS)

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