Wu Zhen, Yang Bin, Liu Chunxia, Liang Ge, Eckenhoff Maryellen F, Liu Weixia, Pickup Stephen, Meng Qingcheng, Tian Yuke, Li Shitong, Wei Huafeng
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Alzheimer Dis Assoc Disord. 2015 Jul-Sep;29(3):184-191. doi: 10.1097/WAD.0000000000000075.
In this study, we investigated the long-term treatment of dantrolene on amyloid and tau neuropathology, brain volume, and cognitive function in aged triple transgenic Alzheimer (3xTg-AD) mice. Fifteen-month old 3xTg-AD mice and wild-type controls were treated with oral dantrolene (5 mg/kg) or vehicle control twice a week for 6 months. Learning and memory were examined using the Morris Water Maze at 21 and 22 months of age. After the behavioral testing, hippocampal and cortical brain volumes were calculated with magnetic resonance imaging and motor function was evaluated using the rotorod. The amyloid burden and tau neurofibrillary tangles in the hippocampus were determined using immunohistochemistry. We found that dantrolene significantly decreased the intraneuronal amyloid accumulation by as much as 76% compared with its corresponding vehicle control, together with a trend to reduce phosphorylated tau in the hippocampus. No significant differences could be detected in hippocampal or cortical brain volume, motor function or cognition among all experimental groups, indicating that the mice were still presymptomatic for Alzheimer disease. Thus, presymptomatic and long-term dantrolene treatment significantly decreased the intraneuronal amyloid burden in aged 3xTg-AD mice before significant changes in brain volume, or cognition.
在本研究中，我们调查了丹曲林对老年三重转基因阿尔茨海默病（3xTg-AD）小鼠淀粉样蛋白和tau神经病理学、脑容量及认知功能的长期治疗效果。15月龄的3xTg-AD小鼠和野生型对照小鼠每周接受两次口服丹曲林（5毫克/千克）或赋形剂对照处理，持续6个月。在21和22月龄时使用莫里斯水迷宫检测学习和记忆能力。行为测试后，用磁共振成像计算海马体和皮质的脑容量，并用转棒试验评估运动功能。采用免疫组织化学法测定海马体中的淀粉样蛋白负荷和tau神经原纤维缠结。我们发现，与相应的赋形剂对照相比，丹曲林可使神经元内淀粉样蛋白积累显著减少多达76%，同时海马体中磷酸化tau有减少趋势。所有实验组在海马体或皮质脑容量、运动功能或认知方面均未检测到显著差异，表明这些小鼠仍处于阿尔茨海默病的症状前期。因此，症状前期长期使用丹曲林治疗可在脑容量或认知出现显著变化之前，显著降低老年3xTg-AD小鼠神经元内的淀粉样蛋白负荷。
