Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of senile dementia in the United States. Accumulation of amyloid-b (Ab) and the effects of this peptide on microglial cells contribute greatly to the etiology of AD. Experiments were carried out to determine whether the panselective s-receptor agonist afobazole can modulate microglial response to the cytotoxic Ab fragment, Ab [25][26][27][28][29][30][31][32][33][34][35] . Treatment with afobazole decreased microglial activation in response to Ab, as indicated by reduced membrane ruffling and cell migration. The effects of afobazole on Ab 25-35 -evoked migration were concentration dependent and consistent with s-receptor activation. When afobazole was coapplied with either BD-1047 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide] or rimcazole, which are s-1-and s-2-selective antagonists, respectively, the inhibition of Ab 25-35 -induced migration by afobazole was reduced. Prolonged exposure of microglia to Ab 25-35 resulted in glial cell death that was associated with increased expression of the proapoptotic protein Bax and the death protease caspase-3. Coapplication of afobazole with Ab 25-35 decreased the number of cells expressing both Bax and caspase-3 and resulted in a concomitant enhancement in cell survival. Although afobazole inhibited activation of microglia cells by Ab [25][26][27][28][29][30][31][32][33][34][35] , it preserved normal functional responses in these cells after exposure to the amyloid peptide. Intracellular calcium increases induced by ATP were depressed in microglia after 24-hour exposure to Ab [25][26][27][28][29][30][31][32][33][34][35] . However, coincubation in afobazole returned these responses to near control levels. Therefore, stimulation of s-1 and s-2 receptors by afobazole prevents Ab [25][26][27][28][29][30][31][32][33][34][35] activation of microglia and inhibits Ab 25-35 -associated cytotoxicity, suggesting that afobazole may be useful for AD therapeutics.

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