Creeley Catherine, Wozniak David F, Labruyere Joanne, Taylor George T, Olney John W
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2006 Apr 12;26(15):3923-32. doi: 10.1523/JNEUROSCI.4883-05.2006.
Memantine, a drug recently approved for treatment of Alzheimer's disease, has been characterized as a unique NMDA antagonist that confers protection against excitotoxic neurodegeneration without the serious side effects that other NMDA antagonists are known to cause. In the present study, we determined what dose of memantine is required to protect the adult rat brain against an NMDA receptor-mediated excitotoxic process and then tested that dose and a range of lower doses to determine whether the drug in this dose range is associated with significant side effects. Consistent with previous research, we found that memantine confers a neuroprotective effect beginning at an intraperitoneal dose of 20 mg/kg, a dose that we found, contrary to previous reports, produces locomotor disturbances severe enough to preclude testing for learning and memory effects. We then determined that, at intraperitoneal doses of 10 and 5 mg/kg, memantine disrupts both memory and locomotor behaviors. Rats treated with these doses performed at control-like levels in learning a hole-board task but were significantly impaired in demonstrating what they had learned when tested 24 h later. This impairment of memory retention was not state dependent in that it was demonstrable regardless of whether the rats were or were not exposed to memantine on the day of retention testing. We conclude that, in the adult rat, memantine behaves like other NMDA antagonists in that it is neuroprotective only at doses that produce intolerable side effects, including memory impairment.
美金刚是一种最近被批准用于治疗阿尔茨海默病的药物，它被认为是一种独特的N-甲基-D-天冬氨酸（NMDA）拮抗剂，能在不产生其他已知NMDA拮抗剂所引发的严重副作用的情况下，对兴奋性毒性神经变性起到保护作用。在本研究中，我们确定了需要多大剂量的美金刚才能保护成年大鼠大脑免受NMDA受体介导的兴奋性毒性过程的影响，然后测试了该剂量以及一系列更低的剂量，以确定该剂量范围内的药物是否会产生显著的副作用。与先前的研究一致，我们发现美金刚从腹腔注射剂量为20mg/kg开始就具有神经保护作用，但我们发现，与先前的报道相反，这个剂量会产生严重到足以妨碍对学习和记忆效应进行测试的运动障碍。然后我们确定，腹腔注射剂量为10mg/kg和5mg/kg时，美金刚会干扰记忆和运动行为。用这些剂量治疗的大鼠在学习洞板任务时表现与对照组相似，但在24小时后测试它们所学内容时，表现明显受损。这种记忆保持的损害并非状态依赖性的，因为无论在记忆测试当天大鼠是否接触美金刚，这种损害都能表现出来。我们得出结论，在成年大鼠中，美金刚的作用与其他NMDA拮抗剂类似，即只有在产生包括记忆损害在内的无法耐受的副作用的剂量下才具有神经保护作用。
