Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1-40)
Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1-40)
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DOI：
10.1016/s0006-8993(02)03731-9
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发表时间：
2002-12-20
期刊：
影响因子：
2.9
通讯作者：
Quack, G
中科院分区：
文献类型：
--
作者：
Miguel-Hidalgo, JJ;Alvarez, XA;Quack, G
P-淀粉样蛋白增强的兴奋性毒性可能会加剧阿尔茨海默病 (AD) 中的进行性神经元丧失和认知能力下降。美金刚是一种非竞争性 NMDA 受体拮抗剂，正在临床开发中用于治疗 AD。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，我们确定了美金刚是否可以预防 P-淀粉样蛋白引起的大鼠神经毒性和学习障碍。 20 只 Sprague-Dawley 大鼠接受载体或载体加美金刚（稳态血浆浓度 2.34+/-0.23 muM，n=10）皮下注射。通过渗透泵持续9天。治疗2天后，将2μl含有β-淀粉样蛋白1-40[Abeta(1-40)]的水注入海马裂中。在治疗的第九天，处死动物，并使用形态学和免疫组织化学技术来确定海马神经元变性以及星形胶质细胞和小胶质细胞活化的程度。在治疗第八天测试精神运动活动和空间辨别力。向海马注射 Abeta(1-40)，但不是水，会导致 CA1 亚区神经元损失，出现广泛细胞凋亡以及星形胶质细胞和小胶质细胞活化和肥大的证据。与载体治疗的动物相比，美金刚治疗的动物神经元变性、核固缩和GFAP免疫染色的数量显着减少。这些数据表明，治疗相关浓度的美金刚可以防止 P-淀粉样蛋白诱导的神经元变性。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Progressive neuronal loss and cognitive decline in Alzheimer's disease (AD) might be aggravated by P-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 P-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 muM, n=10) s.c. by osmotic pump for 9 days. After 2 days of treatment, 2 mul 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 CAl 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 P-amyloid. (C) 2002 Elsevier Science B.V. All rights reserved.