Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
Department of Anatomy and Cell Biology, McGill University, Montreal, Canada.
Alzheimers Dement. 2018 Jun;14(6):811-823. doi: 10.1016/j.jalz.2017.11.009. Epub 2017 Dec 29.
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.
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.
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.
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.
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。
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。
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。
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。
