title: Stimulation of sigma receptors with afobazole blocks activation of microglia and reduces toxicity caused by amyloid-β25-35.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of senile dementia in the United States. Accumulation of amyloid-β (Aβ) and the effects of this peptide on microglial cells contribute greatly to the etiology of AD. Experiments were carried out to determine whether the pan-selective σ-receptor agonist afobazole can modulate microglial response to the cytotoxic Aβ fragment, Aβ25-35. Treatment with afobazole decreased microglial activation in response to Aβ, as indicated by reduced membrane ruffling and cell migration. The effects of afobazole on Aβ25-35-evoked migration were concentration dependent and consistent with σ-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 σ-1- and σ-2-selective antagonists, respectively, the inhibition of Aβ25-35-induced migration by afobazole was reduced. Prolonged exposure of microglia to Aβ25-35 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 Aβ25-35 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 Aβ25-35, 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 Aβ25-35. However, coincubation in afobazole returned these responses to near control levels. Therefore, stimulation of σ-1 and σ-2 receptors by afobazole prevents Aβ25-35 activation of microglia and inhibits Aβ25-35-associated cytotoxicity, suggesting that afobazole may be useful for AD therapeutics.
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine, Tampa, Florida (A.A.B., J.C.); IBC Generium, Volginsky, Russian Federation (I.E.Y., A.M.S., S.B.S.); and Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russian Federation (S.B.S.).
authors.forename: Adam A
authors.initials: AA
authors.lastname: Behensky
authors.forename: Ilya E
authors.initials: IE
authors.lastname: Yasny
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Shuster
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Seredenin
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Petrov
authors.forename: Javier
authors.initials: J
authors.lastname: Cuevas
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors
chemical_list: C410924:2-((2-morpholino)ethylthio)-5-ethoxybenzimidazole; D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D001562:Benzimidazoles; D009025:Morpholines; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; C074636:amyloid beta-protein (25-35); D002118:Calcium