Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease
Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease
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DOI：
10.1159/000051227
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发表时间：
2000-01-01
影响因子：
2.4
通讯作者：
Maelicke, A
中科院分区：
文献类型：
--
作者：
Maelicke, A
中枢胆碱能系统的损伤在阿尔茨海默病（AD）患者的认知能力下降中起着关键作用。最突出的胆碱能缺陷之一是大脑中烟碱乙酰胆碱受体（nAChR）数量减少。由于这些受体对记忆和学习很重要，因此增强烟碱神经传递是AD的一种有前途的治疗策略。纠正这些胆碱能缺陷的两种最常见的方法是通过抑制乙酰胆碱酯酶（AChE）来增加乙酰胆碱（ACh）的突触可用性，或通过直接作用于烟碱受体来模拟ACh（烟碱激动剂）的作用。临床研究表明，乙酰胆碱酯酶抑制剂只产生短期的症状改善。类似地，长期使用烟碱激动剂可能诱导烟碱受体脱敏，导致耐受性，从而限制疗效持续时间。nAChR的变构调节是一种新的方法，它可以避免耐受的发展。变构调节剂结合到nAChR上的一个位点，该位点不同于天然激动剂ACh的结合位点。这种变构相互作用放大了ACh在突触后和突触前nAChR的作用。特别是，突触前nAChR能够调节ACh和其他神经递质，如谷氨酸，血清素和GABA的释放，这可能有助于疾病的症状。因此，nAChR的变构调节可以在AD中产生显著的治疗益处。这些变构调节剂中最有效的一种是加兰他敏。除了调节nAChR，加兰他敏还抑制AChE。加兰他敏的临床获益在多大程度上归因于其烟碱效应尚不确定，需要进一步研究。然而，加兰他敏维持患者的认知和日常功能水平至少1年，这是其他AChE抑制剂尚未报道的。加兰他敏对nAChR的调节作用可能影响转录调节，导致nAChR合成增加。这可能是加兰他敏持续有效的原因。版权所有（C）2000 S. Karger AG，巴塞尔。
Impairment of the central cholinergic system has a pivotal role in the cognitive decline observed in patients with Alzheimer's disease (AD). One of the most prominent cholinergic deficits is the reduced number of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are important for memory and learning, enhancing nicotinic neurotransmission is a promising treatment strategy for AD. The two most common ap preaches to correcting these cholinergic deficits are to increase the synaptic availability of acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE), or to mimic the effects of ACh (nicotinic agonists) by acting directly on nicotinic receptors. Clinical studies suggest that AChE inhibitors produce only short-term symptomatic improvement. Similarly, long-term use of nicotinic agonists may induce desensitization of nicotinic receptors, leading to tolerance and therefore limiting the duration of efficacy. Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance. Allosteric modulators bind to a site on nAChR that is different to the binding site of the natural agonist, ACh. This allosteric interaction amplifies the actions of ACh at post- and presynaptic nAChR. In particular, presynaptic nAChR are capable of modulating the release of ACh and other neurotransmitters, such as glutamate, serotonin and GABA, which may contribute to symptoms of the illness. Allosteric modulation of nAChR could therefore produce significant therapeutic benefit in AD. One of the most potent of these allosteric modulators is galantamine. As well as modulating nAChR, galantamine inhibits AChE. The extent to which the clinical benefits of galantamine are attributable specifically to its nicotinic effects is uncertain and requires further investigation. However, galantamine maintains patients' level of cognitive and daily function for at least 1 year, which has not been reported for other AChE inhibitors. Galantamine's modulatory effects on nAChR may influence transcriptional regulation, resulting in an increased synthesis of nAChR. This may account for galantamine's sustained efficacy. Copyright (C) 2000 S. Karger AG, Basel.