Ingram D K, Spangler E L, Iijima S, Ikari H, Kuo H, Greig N H, London E D
Nathan W. Shock Laboratories, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
Life Sci. 1994;55(25-26):2037-49. doi: 10.1016/0024-3205(94)00384-x.
The Stone maze paradigm has been developed for use as a rat model of memory impairment observed in normal aging and in Alzheimer's disease. Results from several studies have demonstrated the involvement of both cholinergic and glutamatergic systems in acquisition performance in this complex maze task. Although results of clinical studies on the cognitive enhancing abilities of cholinomimetics for treatment of memory impairment in Alzheimer's disease have been inconsistent, new classes of cholinesterase inhibitors offer greater potential for therapeutic efficacy. The physostigimine derivative, phenserine, appears to have marked efficacy for improving learning performance of aged rats or of young rats treated with scopolamine in the Stone maze. Declines in markers of glutamatergic neurotransmission in Alzheimer's disease and in normal aging suggest that pharmacological manipulation of this system might also prove beneficial for cognitive enhancement. Treatment with glycine and/or polyamine agonists is suggested as a strategy for activating the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, the use of combined pharmacological activation of cholinergic and glutamatergic systems is suggested. Manipulation of signal transduction events should also be considered as a strategy for cognitive enhancement. The influx of Ca2+ through the channel formed by the NMDA receptor stimulates the production of the oxyradical, nitric oxide (NO*), via the action of nitric oxide synthase (NOS). Compounds that inhibit NOS activity impair acquisition in the Stone maze, suggesting an involvement of NO*. Thus, strategies for inducing NO* production to enhance cognitive performance may be beneficial. Because of the potential neurotoxicity for NO*, this strategy is not straightforward. Although many new directions beyond the cholinergic hypothesis can be suggested, each has its potential benefits which must be weighed against its risks. Nonetheless, an important unifying area for neurobiological research examining mechanisms of normal brain aging and of age-related neuropathology, as observed in Alzheimer's disease, might emerge from the identification of NO* as a simple molecule serving vital physiological functions but representing potential for neurotoxicity.
石迷宫范式已被开发用作正常衰老和阿尔茨海默病中观察到的记忆障碍的大鼠模型。多项研究结果表明，胆碱能系统和谷氨酸能系统均参与了这一复杂迷宫任务中的习得表现。尽管关于拟胆碱药治疗阿尔茨海默病记忆障碍的认知增强能力的临床研究结果并不一致，但新型胆碱酯酶抑制剂具有更大的治疗效果潜力。毒扁豆碱衍生物苯丝氨酸似乎对改善老年大鼠或用东莨菪碱处理的年轻大鼠在石迷宫中的学习表现具有显著效果。阿尔茨海默病和正常衰老中谷氨酸能神经传递标志物的下降表明，对该系统进行药理学操作可能也有利于认知增强。建议使用甘氨酸和/或多胺激动剂作为激活谷氨酸受体N-甲基-D-天冬氨酸（NMDA）亚型的策略。此外，建议联合使用胆碱能和谷氨酸能系统的药理学激活方法。信号转导事件的操作也应被视为一种认知增强策略。钙离子通过NMDA受体形成的通道内流，通过一氧化氮合酶（NOS）的作用刺激氧自由基一氧化氮（NO*）的产生。抑制NOS活性的化合物会损害在石迷宫中的习得，表明NO参与其中。因此，诱导NO产生以增强认知表现的策略可能是有益的。由于NO具有潜在的神经毒性，这一策略并不简单。尽管可以提出许多超出胆碱能假说的新方向，但每个方向都有其潜在的益处，必须权衡其风险。尽管如此，通过将NO鉴定为一个具有重要生理功能但具有神经毒性潜力的简单分子，可能会出现一个重要的统一领域，用于神经生物学研究，以研究正常脑衰老和阿尔茨海默病中与年龄相关的神经病理学机制。
