Perez Sylvia E, Nadeem Muhammad, Sadleir Katherine R, Matras Joanna, Kelley Christy M, Counts Scott E, Vassar Robert, Mufson Elliott J
Department of Neurological Sciences, Rush University Medical Center Chicago, IL 60612.
Int J Physiol Pathophysiol Pharmacol. 2012;4(3):115-27. Epub 2012 Sep 20.
A double blind, placebo-controlled phase II study revealed that the antihistamine, Dimebon® (dimebolin, latrepirdine) improved cognition in Alzheimer disease (AD) patients compared to placebo controls. However, the Phase III CONNECTION trial failed to demonstrate significant differences between dimebon and placebo treatments. Despite the controversial therapeutic outcomes in the treatment of AD, dimebon's mechanism(s) of action within the brain remain unclear. In the present study, we evaluated the effects of dimebon upon β-amyloid (Aβ), tau and astrocytes in the hippocampus of triple transgenic (3xTg-AD) mice, which develop AD-like pathology in an age-dependent manner. At age 6.5 months, prior to the development of Aβ plaques in the hippocampus, male and female 3xTg-AD mice, received a daily intraperitoneal injection of 0.1 % dimebon or saline for 1.5 months. At 8 months, quantitative immunohistochemistry revealed a significant reduction in hippocampal/subicular APP/Aβ in dimebon-treated mice, whereas protein bioassay found no change in full length APP, soluble Aβ(1-40) and Aβ(1-42), Aβ oligomers, BACE1 and GFAP levels between groups. Interestingly, the number of the hippocampal APP/Aβ plaques in female and male dimebon-treated mice was higher compared to gender-matched control mice. Dimebon did not alter hippocampal tau levels. Furthermore, dimebon protects SH-SY5Y neurons against Aβ toxicity and promotes GFAP expression in primary mouse astrocyte cultures. Our findings demonstrate that dimebon in vivo modifies hippocampal APP/Aβ pathology and in vitro protects against Aβ toxicity promoting cell survival and activates astrocytes.
一项双盲、安慰剂对照的II期研究表明，与安慰剂对照组相比，抗组胺药Dimebon®（地美环素，拉曲必利）可改善阿尔茨海默病（AD）患者的认知能力。然而，III期CONNECTION试验未能证明Dimebon与安慰剂治疗之间存在显著差异。尽管在AD治疗中治疗结果存在争议，但Dimebon在大脑中的作用机制仍不清楚。在本研究中，我们评估了Dimebon对三联转基因（3xTg-AD）小鼠海马中β-淀粉样蛋白（Aβ）、tau蛋白和星形胶质细胞的影响，该小鼠以年龄依赖性方式发展出AD样病理。在6.5个月大时，即在海马中出现Aβ斑块之前，对雄性和雌性3xTg-AD小鼠每天腹腔注射0.1%的Dimebon或生理盐水，持续1.5个月。在8个月时，定量免疫组织化学显示，Dimebon治疗的小鼠海马/海马下区APP/Aβ显著减少，而蛋白质生物测定发现各组之间全长APP、可溶性Aβ(1-40)和Aβ(1-42)、Aβ寡聚体、BACE-Ⅰ和GFAP水平没有变化。有趣的是，与性别匹配的对照小鼠相比，Dimebon治疗的雄性和雌性小鼠海马APP/Aβ斑块数量更多。Dimebon没有改变海马tau蛋白水平。此外，Dimebon可保护SH-SY5Y神经元免受Aβ毒性，并促进原代小鼠星形胶质细胞培养物中GFAP的表达。我们的数据表明，Dimebon在体内可改变海马APP/Aβ病理，在体外可保护细胞免受Aβ毒性，促进细胞存活并激活星形胶质细胞。
