N-methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against β-amyloid neurotoxicity
N-methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against β-amyloid neurotoxicity
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DOI：
10.1006/nbdi.1998.0230
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发表时间：
1999-04-01
影响因子：
6.1
通讯作者：
Nyakas, C
中科院分区：
文献类型：
--
作者：
Harkany, T;Mulder, J;Nyakas, C
先前的实验数据表明，在β-淀粉样蛋白（β A）神经毒性中，可能由N-甲基-D-天冬氨酸（NMDA）受体介导的Ca 2+相关兴奋性毒性过程参与其中。另一方面，其他证据支持自由基生成是β A诱导的神经退行性级联反应中的关键步骤的观点。因此，在本研究中，应用神经保护策略来探索这些通路中的每一个在β A毒性中的贡献。将β A（（1-42））注入大鼠基底核大细胞内，同时单独或联合给予NMDA受体拮抗剂MK-801（2.5mg/kg）和/或维生素E和C复合物（150 mg/kg）来实现神经保护。通过在连续系列的行为任务中测试动物来确定神经变性的程度，所述行为任务包括高架十字迷宫、被动回避学习、小旷场和旷场范例，随后是乙酰胆碱酯酶（AChE）、胆碱乙酰转移酶（ChAT）和超氧化物歧化酶（SOD）生化。在基底核中注射β A在高架十字迷宫中引起显著的焦虑，被动回避学习的紊乱，以及在两个开放领域任务中自发行为的改变。AChE和ChAT的显著降低伴随着MnSOD的类似降低，但Cu/ZnSOD的降低不提供行为改变的神经化学底物。每一种单药给药保护免受神经毒性事件，而联合治疗未能改善β A毒性。(C)北京：科学出版社.
Previous experimental data indicate the involvement of Ca2+-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the beta A-induced neurodegenerative cascade. In the present study, therefore, a neuroprotective strategy was applied to explore the contributions of each of these pathways in beta A toxicity. beta A((1-42)) was injected into the magnocellular nucleus basalis of rats, while neuroprotection was achieved by either single or combined administration of the NMDA receptor antagonist MK-801 (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of neurodegeneration was determined by testing the animals in consecutive series of behavioral tasks, including elevated plus maze, passive avoidance learning, small open-field and open-field paradigms, followed by acetylcholinesterase (AChE), cholineacetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry, beta A injected in the nucleus basalis elicited significant anxiety in the elevated plus maze, derangement of passive avoidance learning, and altered spontaneous behaviors in both open-field tasks. A significant decrease in both AChE and ChAT accompanied by a similar decrement of MnSOD, but not of Cu/ZnSOD provided neurochemical substrates for the behavioral changes, Each of the single drug administrations protected against the neurotoxic events, whereas the combined treatment failed to ameliorate beta A toxicity. (C) 1999 Academic Press.