On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease
On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease
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DOI：
10.1016/j.mehy.2005.03.011
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发表时间：
2005-01-01
影响因子：
4.7
通讯作者：
Schmitt, HP
中科院分区：
文献类型：
--
作者：
Schmitt, HP
美金刚等离子通道阻滞剂（ICB）作用于NMDA和其他胺能递质受体，对阿尔茨海默病（AD）具有令人惊讶的有益作用，但人们对此知之甚少。AD患者的NMDA受体水平和结合率显著降低，其中高度NMDA受体和Ca 2+依赖性突触可塑性和重塑严重受损。因此，人们如何期望通过用拮抗剂进一步抑制NMDA通道来改善AD。然而，NMDA受体阻滞剂的临床试验显示，在中度至晚期AD令人惊讶的积极作用。本文试图对国际商品银行这种自相矛盾的成功提供一种假设性的解释。根据目前的数据证据，重点放在一个深刻的损害AD大脑的抑制-兴奋平衡的神经元回路的优势，激励。这种不平衡被认为是由四种调节性胺能递质系统（5-羟色胺、去甲肾上腺素、乙酰胆碱、组胺）和相关肽能系统的退化引起的，其下降导致前脑神经元回路中抑制作用的严重丧失，导致主要神经元的去抑制（“胺能去抑制”）。由此产生的Ca ~（2+）兴奋毒性及其后遗症是AD神经退行性变及相关智力下降的基本促进因素。通过减少兴奋来重新调节抑制-兴奋失衡被认为是使离子通道阻滞在治疗上成功的机制。脓毒症，试图增加抑制，例如，通过应用GABA模拟物刺激从保存但缺乏胺能易化的“懒惰”GABA神经元产生GABA，可能是实现再平衡的更好方式。(c)2005爱思唯尔有限公司保留所有权利。
The surprisingly beneficial effects in Alzheimer disease (AD) of ion channel blockers (ICB) like memantine that act on NMDA- and other aminergic transmitter receptors are yet poorly understood. NMDA receptor levels and binding were shown to be significantly decreased in AD, in which highly NMDA receptor and Ca2+ dependent synaptic plasticity and re-modelling are severely compromised. Thus, how could one expect to improve AD by further suppressing NMDA channels with antagonists. Nevertheless, clinical trials with NMDA blockers revealed in moderate to advanced AD surprisingly positive effects. The present paper tries to provides a hypothetical explanation of that paradoxical success of ICBs. Based on evidence from current data, emphasis is put on a profound impairment in the AD brain of the inhibition-excitation balance in the neuronal circuitry to the advantage of excitation. This imbalance is conceived to result from a degeneration of four modulatory aminiergic transmitter systems (serotonin, noradrenalin, acetylcholine, histamine) and related peptidergic systems, the decline of which causes a profound loss of inhibitory impact in the forebrain neuronal circuitry leading to disinhibition of principal neurones ("aminergic disinhibition"). Subsequent Ca2+ excito-toxicity and its sequelae are suggested to be the basic promotors of the neuro-degeneration and the related mental decline in AD. Re-adjustment of the inhibition-excitation imbalance by decreasing excitation is conceived to be the mechanism that renders ion channel blockade therapeutically successful. Putatively, attempts to increase inhibition, e.g., by application of GABA mimetics that stimulate the production GABA from preserved but "lazy" GABA neurones lacking aminergic facilitation, might be an even better way to achieve the re-balance. (c) 2005 Elsevier Ltd. All rights reserved.