Miguel-Hidalgo J J, Alvarez X A, Cacabelos R, Quack G
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
Brain Res. 2002 Dec 20;958(1):210-21. doi: 10.1016/s0006-8993(02)03731-9.
Progressive neuronal loss and cognitive decline in Alzheimer's disease (AD) might be aggravated by beta-amyloid-enhanced excitotoxicity. Memantine is an uncompetitive NMDA receptor antagonist under clinical development for the treatment of AD. Memantine has neuroprotective actions in several in vitro and in vivo models. In the present study, we determined whether memantine protected against beta-amyloid induced neurotoxicity and learning impairment in rats. Twenty Sprague-Dawley rats received vehicle or vehicle plus memantine (steady-state plasma concentrations of 2.34+/-0.23 microM, n=10) s.c. by osmotic pump for 9 days. After 2 days of treatment, 2 microl of water containing beta-amyloid 1-40 [Abeta(1-40)] were injected into the hippocampal fissure. On the ninth day of treatment, animals were sacrificed, and morphological and immunohistochemical techniques were used to determine the extent of neuronal degeneration and astrocytic and microglial activation in the hippocampus. Psychomotor activity and spatial discrimination were tested on the eighth day of treatment. Abeta(1-40), but not water, injections into hippocampus led to neuronal loss in the CA1 subfield, evidence of widespread apoptosis, and astrocytic and microglial activation and hypertrophy. Memantine treated animals had significant reductions in the amount of neuronal degeneration, pyknotic nuclei, and GFAP immunostaining as compared with vehicle treated animals. These data suggest that memantine, at therapeutically relevant concentrations, can protect against neuronal degeneration induced by beta-amyloid.
阿尔茨海默病（AD）中进行性的神经元丧失和认知衰退可能会因β-淀粉样蛋白增强的兴奋性毒性而加重。美金刚是一种正在进行临床开发用于治疗AD的非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。美金刚在多种体外和体内模型中具有神经保护作用。在本研究中，我们确定美金刚是否能保护大鼠免受β-淀粉样蛋白诱导的神经毒性和学习障碍。20只Sprague-Dawley大鼠通过渗透泵皮下注射溶剂或溶剂加美金刚（稳态血浆浓度为2.34±0.23微摩尔，n = 10），持续9天。治疗2天后，将2微升含β-淀粉样蛋白1-40 [Aβ(1-40)]的水注入海马裂。在治疗的第9天，处死动物，并用形态学和免疫组织化学技术确定海马中神经元变性、星形胶质细胞和小胶质细胞活化的程度。在治疗的第8天测试精神运动活动和空间辨别能力。向海马注射Aβ(1-40)而非水会导致CA1亚区神经元丧失、广泛凋亡的证据以及星形胶质细胞和小胶质细胞活化及肥大。与溶剂处理的动物相比，美金刚处理的动物在神经元变性、固缩核和胶质纤维酸性蛋白（GFAP）免疫染色量方面有显著减少。这些数据表明，在治疗相关浓度下，美金刚可以保护免受β-淀粉样蛋白诱导的神经元变性。
