Afobazole activation of σ-1 receptors modulates neuronal responses to amyloid-β25-35 - PubMed (original) (raw)

. 2013 Nov;347(2):468-77.

doi: 10.1124/jpet.113.208330. Epub 2013 Sep 4.

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Afobazole activation of σ-1 receptors modulates neuronal responses to amyloid-β25-35

Adam A Behensky et al. J Pharmacol Exp Ther. 2013 Nov.

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.

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