Narahashi Toshio, Moriguchi Shigeki, Zhao Xilong, Marszalec William, Yeh Jay Zeus
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA.
Biol Pharm Bull. 2004 Nov;27(11):1701-6. doi: 10.1248/bpb.27.1701.
No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer's patients. Nefiracetam has been shown to potentiate ACh currents in the alpha4beta2 receptor of rat cortical neurons with a bell-shaped dose-response relationship and the maximum effect at 1 nM. This effect was exerted via G(s) proteins. The alpha7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the alpha4beta2 receptor and potentiated NMDA currents with the maximum effect at 1 microM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1-10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients' learning, cognition, and memory.
由于我们尚不清楚阿尔茨海默病的确切病因，所以尚未开发出治愈该病的策略。目前患者唯一可用的治疗方法是对症治疗。由于阿尔茨海默病与大脑中胆碱能系统的下调有关，因此刺激该系统有望改善患者的认知、学习和记忆能力。在美国，已有四种抗胆碱酯酶药物被批准用于治疗阿尔茨海默病患者。然而，由于这些药物抑制胆碱酯酶，所以存在副作用，且疗效维持时间不长。因此，需要新的治疗方法。一种方法是直接刺激大脑中的烟碱型乙酰胆碱（nACh）受体，另一种方法是刺激N-甲基-D-天冬氨酸（NMDA）受体，已知该受体在阿尔茨海默病患者中也会下调。已证明奈非西坦能增强大鼠皮层神经元α4β2受体中的乙酰胆碱电流，呈钟形剂量反应关系，在1 nM时效果最佳。这种作用是通过G(s)蛋白实现的。α7受体几乎不受奈非西坦影响。奈非西坦还能增强NMDA电流，在10 nM时效果最佳，其作用是通过与受体的甘氨酸结合位点相互作用实现的。加兰他敏对α4β2受体有中等程度的增强作用，能增强NMDA电流，在1 μM时效果最佳。然而，加兰他敏不与甘氨酸结合位点相互作用。多奈哌齐是一种强效抗胆碱酯酶药物，在1 - 10000 nM时也能增强NMDA电流。总之，这三种药物不仅能增强胆碱能系统的活性，还能增强NMDA系统的活性，从而刺激下调的nACh受体和NMDA受体，改善患者的学习、认知和记忆能力。
