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.).
J Pharmacol Exp Ther. 2013 Nov;347(2):468-77. doi: 10.1124/jpet.113.208330. Epub 2013 Sep 4.
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.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是认知功能持续下降。目前还没有发现能够有效阻止或逆转其进展的治疗方法。AD 的一个标志是淀粉样β肽（Aβ）的积累，Aβ 仅通过多种机制诱导神经元损伤。这里呈现的数据表明，大鼠皮质神经元长时间（1-24 小时）暴露于 Aβ25-35 会导致基础细胞内 Ca(2+)浓度([Ca(2+)]i)增加，而同时共培养化合物阿法佐三嗪可抑制这些 [Ca(2+)]i 增加。阿法佐三嗪对 [Ca(2+)]i 的作用归因于 σ-1 受体的激活，但第二泛选择性 σ 受体激动剂 1,3-二-o-甲苯基胍（DTG）不能模拟该作用。还发现阿法佐三嗪可减轻 Aβ25-35 应用引起的一氧化氮（NO）产生，但不影响 Aβ 片段引起的活性氧升高。阿法佐三嗪引起的 [Ca(2+)]i 降低和 NO 紊乱与神经元细胞死亡减少有关，而 DTG 未能增强细胞存活。检查涉及神经元存活增加的分子机制表明，阿法佐三嗪孵育导致促凋亡蛋白 Bax 和死亡蛋白酶 caspase-3 的表达降低，同时增加抗凋亡蛋白 Bcl-2 的表达。鉴于 Aβ 神经毒性在 AD 发病机制中的重要性，这里报道的发现表明阿法佐三嗪可能是一种有效的 AD 治疗剂。此外，σ-1 受体可能是 AD 治疗的有用靶点，尽管并非所有 σ 配体似乎都同样有益。
