AF710B，一种 M1/ sigma-1 受体激动剂，在阿尔茨海默病转基因大鼠模型中具有持久的疾病修饰特性。
AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer's disease.
机构信息
Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.
出版信息
Alzheimers Dement. 2018 Jun;14(6):811-823. doi: 10.1016/j.jalz.2017.11.009. Epub 2017 Dec 29.
INTRODUCTION
AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3×Tg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats.
METHODS
Chronic treatment with AF710B (10 μg/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4.5 months and interrupted 5 weeks before behavioral testing.
RESULTS
AF710B long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment.
DISCUSSION
With M1/sigma-1 activity and long-lasting disease-modifying properties at low dose, AF710B is a promising novel therapeutic agent for treating Alzheimer's disease.
简介
AF710B（又名 ANAVEX 3-71）是一种新型选择性变构 M1 毒蕈碱和 sigma-1 受体激动剂。在 3×Tg-AD 小鼠中，AF710B 可减轻认知障碍并减少阿尔茨海默病样特征。我们现在报告 AF710B 在 McGill-R-Thy1-APP 转基因（Tg）大鼠中的长期疾病修饰特性。
方法
在斑块形成后 13 个月的 Tg 大鼠中开始用 AF710B（10μg/kg）进行慢性治疗。药物或载体每天口服给药 4.5 个月，在行为测试前中断 5 周。
结果
AF710B 长期治疗可逆转与 Tg 大鼠晚期阿尔茨海默病样淀粉样神经病理学相关的认知障碍。这些作用伴随着淀粉样蛋白病理学和神经炎症标志物的减少，以及淀粉样蛋白脑脊液清除率和突触标志物水平的增加。重要的是，这些作用在治疗中断 5 周后仍然存在。
讨论
AF710B 具有 M1/sigma-1 活性和低剂量的长期疾病修饰特性，是治疗阿尔茨海默病的一种很有前途的新型治疗剂。
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