Hussain Rehana Z, Miller-Little William A, Lambracht-Washington Doris, Jaramillo Tom C, Takahashi Masaya, Zhang Shanrong, Fu Min, Cutter Gary R, Hayardeny Liat, Powell Craig M, Rosenberg Roger N, Stüve Olaf
Department of Neurology and Neurotherapeutics, the University of Texas Southwestern Medical Center at Dallas, USA.
Department of Radiology, University of Texas Southwestern Medical Center at Dallas, USA; Advanced Imaging Center, University of Texas Southwestern Medical Center at Dallas, USA.
J Neuroimmunol. 2017 Aug 15;309:100-110. doi: 10.1016/j.jneuroim.2017.05.017. Epub 2017 May 26.
Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aβ) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease.
Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10months between ages 4 and 14months with laquinimod (5, 10, or 25mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aβ deposition and tau phosphorylation were determined by immunohistochemistry.
In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by laquinimod.
This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.
拉喹莫德是一种具有良好中枢神经系统（CNS）生物利用度、神经保护和骨髓修复特性的抗炎药。一项针对多发性硬化症患者的临床试验表明，拉喹莫德可显著减少脑容量损失。该治疗效果背后的细胞底物或分子事件尚不清楚。在本研究中，我们旨在探讨拉喹莫德对阿尔茨海默病F1 3xTg-AD/C3H小鼠模型的脑容量、动物行为、细胞数量以及CNS内固有细胞和单核细胞的组成、淀粉样β蛋白（Aβ）积累和tau蛋白磷酸化的潜在影响。
采用剂量反应研究设计，对4个月大的F1 3xTg-AD/C3H小鼠在4至14个月龄期间用拉喹莫德（5、10或25mg/kg）或通过口服灌胃给予磷酸盐缓冲盐水（PBS）治疗10个月。在4个月龄和14个月龄时，使用7特斯拉磁共振成像仪（MRI）测量脑容量。行为测试包括运动和竖毛活动以及莫里斯水迷宫任务。通过多参数流式细胞术评估细胞数量和免疫表型。通过免疫组织化学测定Aβ沉积和tau蛋白磷酸化。
在AD的F1 3xTg-AD/C3H动物模型中，经过10个月的治疗，未检测到脑容量减少，因为安慰剂组或治疗组均未出现脑萎缩。拉喹莫德对大多数神经行为结果没有可检测到的影响。从CNS分离的CNS固有细胞和单核细胞亚群的数量或组成未因拉喹莫德而改变。
这是首次证明在阿尔茨海默病的F1 3xTg-AD/C3H小鼠模型中不存在与年龄相关的脑容量变化。因此，拉喹莫德对本研究的这一结果没有影响。拉喹莫德对行为以及CNS内固有细胞和单核细胞的数量和组成影响的大多数次要结果也均为阴性。
