title: Afobazole activation of σ-1 receptors modulates neuronal responses to amyloid-β25-35.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a continual decline of cognitive function. No therapy has been identified that can effectively halt or reverse its progression. One hallmark of AD is accumulation of the amyloid-β peptide (Aβ), which alone induces neuronal injury via various mechanisms. Data presented here demonstrate that prolonged exposure (1-24 hours) of rat cortical neurons to Aβ25-35 results in an increase in basal intracellular Ca(2+) concentration ([Ca(2+)]i), and that coincubation with the compound afobazole inhibits these [Ca(2+)]i increases. The effect of afobazole on [Ca(2+)]i is due to activation of σ-1 receptors but could not be mimicked by a second pan-selective σ receptor agonist, 1,3-di-o-tolylguanidine (DTG). Afobazole was also found to lessen nitric oxide (NO) production in response to Aβ25-35 application but did not affect elevations in reactive oxygen species elicited by the Aβ fragment. The reductions in [Ca(2+)]i and NO perturbation produced by afobazole were associated with a decrease in neuronal cell death, whereas DTG failed to enhance cell survival. Examining the molecular mechanisms involved in the increased neuronal survival demonstrates that afobazole incubation results in lower expression of the proapoptotic protein Bax and the death protease caspase-3, while at the same time increasing expression of the antiapoptotic protein, Bcl-2. Given the importance of Aβ neurotoxicity in AD etiology, the findings reported here suggest that afobazole may be an effective AD therapeutic agent. Furthermore, σ-1 receptors may represent a useful target for AD treatment, although not all σ ligands appear to be equally beneficial.
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., A.V.P.); 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; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; 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; D000097605:Sigma-1 Receptor
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D001562:Benzimidazoles; D002118:Calcium; D009025:Morpholines; D009569:Nitric Oxide; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C410924:2-((2-morpholino)ethylthio)-5-ethoxybenzimidazole; C074636:amyloid beta-protein (25-35)