Devi Latha, Ohno Masuo
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA.
Pharmacol Biochem Behav. 2016 May;144:60-6. doi: 10.1016/j.pbb.2016.03.002. Epub 2016 Mar 3.
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) β-amyloid (Aβ) accumulation. Treatments with memantine (10mg/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 Aβ oligomer or total Aβ42 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 Aβ as 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 50mg/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 Aβ 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.
美金刚是一种具有神经保护特性的非竞争性 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，已被用于治疗阿尔茨海默病（AD）。据报道，给各种转基因 AD 小鼠施用美金刚可改善认知缺陷，很多时候能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这些巨大益处并未转化为该药物的临床效果，在中度至重度 AD 中仅显示出轻微且短暂的疗效。为了进一步研究体内疗效，我们比较了美金刚在 5XFAD 小鼠不同疾病阶段的作用，5XFAD 小鼠是快速发病且最具侵袭性的淀粉样蛋白模型之一。具体而言，我们对表现出中度（6 - 7 月龄）和大量（12 - 15 月龄）β-淀粉样蛋白（Aβ）积累的 5XFAD 小鼠每天腹腔注射一次美金刚，持续 30 天。通过情境恐惧条件反射和自发交替 Y 迷宫范式测试，美金刚（10mg/kg，腹腔注射）治疗可逆转年轻 5XFAD 小鼠的记忆障碍。美金刚对 5XFAD 小鼠脑内可溶性 Aβ 寡聚体或总 Aβ42 水平没有影响。相比之下，美金刚的亚慢性治疗在老年 5XFAD 组中未显示出行为益处，与年轻 5XFAD 组相比，该组表现出更严重的记忆缺陷，同时 Aβ 浓度大幅升高。由于高剂量（30mg/kg）的亚慢性美金刚会损害野生型对照的记忆表现，我们进一步测试了 50mg/kg 美金刚的急性给药，据报道该剂量可增强海马体成年神经发生和记忆功能。然而，这种治疗也未能挽救 12 - 15 月龄 5XFAD 小鼠的记忆缺陷。总体而言，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，不再观察到美金刚独立于 Aβ 减少的认知益处，这可能反映了美金刚在临床环境中的疗效有限。
