Cognitive benefits of memantine in Alzheimer's 5XFAD model mice decline during advanced disease stages
Cognitive benefits of memantine in Alzheimer's 5XFAD model mice decline during advanced disease stages
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DOI：
10.1016/j.pbb.2016.03.002
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发表时间：
2016-05-01
影响因子：
3.6
通讯作者：
Ohno, Masuo
中科院分区：
文献类型：
--
作者：
Devi, Latha;Ohno, Masuo
美金刚是一种具有神经保护作用的非竞争性NMDA受体拮抗剂，已被用于治疗阿尔茨海默病（AD）。已报道向各种转基因AD小鼠施用美金刚胺可改善认知缺陷，通常完全恢复到正常野生型对照水平。然而，美金刚在临床前研究中的巨大益处并没有转化为这种药物的临床结果，在中度至重度AD中仅显示出边缘和短暂的疗效。为了进一步解决体内功效，我们比较了美金刚在5XFAD小鼠中不同疾病阶段的作用，5XFAD小鼠是快速发作和最具侵袭性的淀粉样蛋白模型之一。具体来说，我们每天一次给5XFAD小鼠施用美金刚胺，持续30天，这些小鼠显示出中度（6-7个月大）和稳健（12-15个月大）的β-淀粉样蛋白（A β）积累。用美金刚（10 mg/kg，i. p.）逆转年轻的5XFAD小鼠的记忆障碍，如通过情境恐惧条件反射和自发交替Y迷宫范例所测试的。美金刚胺对5XFAD小鼠脑中可溶性A β寡聚体或总A β 42水平没有影响。相比之下，用美金刚的亚慢性治疗在较老的5XFAD组中没有表现出行为益处，与较年轻的5XFAD组相比，其表现出更深刻的记忆缺陷，伴随着高度增加的NsA β浓度。由于较高剂量（30 mg/kg）的亚慢性美金刚胺损害了野生型对照的记忆表现，我们进一步测试了50 mg/kg美金刚胺的急性给药，据报道，美金刚胺可增强海马成体神经发生和记忆功能。然而，这种治疗也未能挽救12-15个月大的5XFAD小鼠的记忆缺陷。总的来说，我们的结果表明，在晚期阶段的5XFAD阿尔茨海默病小鼠模型中不再观察到美金刚胺独立于A β减少的认知益处，这可能反映了美金刚胺在临床环境中的有限功效。(C)版权所有© 2016 Elsevier Inc.
Memantine, a noncompetitive NMDA receptor antagonist with neuroprotective properties, has been used for the treatment of Alzheimer's disease (AD). Administration of memantine to various transgenic AD mice has been reported to improve cognitive deficits, very often completely back to normal wild-type control levels. However, such great benefits of memantine in preclinical studies do not translate into clinical results of this drug, showing only marginal and transient efficacy in moderate to severe AD. To further address in vivo efficacy, we compared the effects of memantine at different disease stages in 5XFAD mice, one of the rapid-onset and most aggressive amyloid models. Specifically, we administered memantine once daily for 30 days to 5XFAD mice, which showed moderate (6-7 months of age) and robust (12-15 months) beta-amyloid (A beta) accumulation. Treatments with memantine (10 mg/kg, i.p.) reversed memory impairments in the younger 5XFAD mice, as tested by the contextual fear conditioning and spontaneous alternation Y-maze paradigms. Memantine had no effects on soluble A beta oligomer or total A beta 42 levels in 5XFAD mouse brains. In contrast, subchronic treatments with memantine showed no behavioral benefits in the older 5XFAD group, which exhibited more profound memory deficits concomitant with highly increased concentrations of Ns A beta compared with those of the younger 5XFAD group. Since subchronic memantine at the higher dose (30 mg/kg) impaired memory performances in wild-type controls, we further tested acute administration of 50 mg/kg memantine, which was reported to enhance hippocampal adult neurogenesis and memory function. However, this treatment also failed to rescue memory deficits in 12-15-month-old 5XFAD mice. Collectively, our results demonstrate that cognitive benefits of memantine independent of A beta reductions were no longer observed in the 5XFAD Alzheimer mouse model during advanced stages, which may be reflective of the limited efficacy of memantine in clinical settings. (C) 2016 Elsevier Inc All rights reserved.