Pharmacological effects of Catharanthus roseus root alkaloids in acetylcholinesterase inhibition and cholinergic neurotransmission
Pharmacological effects of Catharanthus roseus root alkaloids in acetylcholinesterase inhibition and cholinergic neurotransmission
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DOI：
10.1016/j.phymed.2009.10.008
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发表时间：
2010-07-01
期刊：
影响因子：
7.9
通讯作者：
Andrade, Paula B.
中科院分区：
文献类型：
--
作者：
Pereira, David M.;Ferreres, Federico;Andrade, Paula B.
长春花的叶子是已知的吲哚单萜生物碱长春新碱和长春碱的唯一来源。在这项工作中，我们研究了根的生物潜力，在几个国家，根被用作治疗许多疾病的草药或热水提取物。水提取物强烈抑制乙酰胆碱酯酶（AchE）在体外微量测定，效果主要归因于蛇纹石（IC 50 = 0.775 μ M vs毒扁豆碱IC 50 = 6.45 μ M）与纯化合物进行评估。使用大鼠离体制剂，即回肠和隔膜/膈神经，分别测试纯生物碱的毒蕈碱和烟碱拮抗作用。丝氨酸竞争性地阻断毒蕈碱受体，其pA（2）为5.2，而前体阿马里辛高达80 μ M时与对照无区别，长春质碱在大于10 μ M浓度时表现出不可克服的毒蕈碱拮抗作用。烟碱受体介导的膈肌收缩完全抑制长春质碱（IC 50 = 59.6 μ M）和ajmalicine（IC 50 = 72.3 μ M），在一个可逆的，但非竞争性的方式，不像更有效的烟碱拮抗剂筒箭毒碱（IC 50 = 0.35 μ M），其竞争性封锁被克服毒扁豆碱诱导的乙酰胆碱增加。seroglycan高达100 μ M并没有改变膈肌收缩，这表明减少神经肌肉烟碱受体的亲和力。尽管在体外强烈的乙酰胆碱酯酶抑制，蛇纹石未能恢复隔膜收缩后，次最大的筒箭毒碱封锁，这表明不良的组织渗透可能会阻止蛇纹石抑制乙酰胆碱酯酶在深层神经肌肉突触的离体制剂。据我们所知，本研究是第一个评估C。蔷薇根提取物，以及蛇纹石，ajmalicine和长春质碱对乙酰胆碱酯酶。本文所述的结果表明，目前被忽视的C玫瑰根可能构成一个有前途的来源的化合物具有药用价值。此外，考虑到蛇纹石的有效的体外AchE抑制活性和低胆碱能受体亲和力，可以想象的是，微小的结构修饰可以产生有效的和选择性的AchE抑制剂，潜在地用于诸如阿尔茨海默病和/或重症肌无力的病症的药理学管理。(C)2009年Elsevier GmbH。All rights reserved.
The leaves of Catharanthus roseus constitute the only source of the well known indolomonoterpenic alkaloids vincristine and vinblastine. In this work we studied the biological potential of the roots, which are used in several countries as decocts or hot water extracts for the treatment of a number of conditions. The aqueous extract strongly inhibited acetylcholinesterase (AchE) in an in vitro microassay, an effect ascribable mainly to serpentine (IC50 = 0.775 mu M vs physostigmine IC50 = 6.45 mu M) as assessed with the pure compound. Pure alkaloids were tested for muscarinic and nicotinic antagonism using rat ex-vivo preparations, namely, ileum and diaphragm/phrenic-nerve, respectively. Serpentine competitively blocked muscarinic receptors with a pA(2) of 5.2, whereas the precursor ajmalicine up to 80 mu M was undistinguishable from control, and catharanthine exhibited an unsurmountable muscarinic antagonism at greater than 10 mu M concentrations. Nicotinic receptor mediated diaphragm contractions were fully inhibited by catharanthine (IC50 = 59.6 mu M) and ajmalicine (IC50 = 72.3 mu M), in a reversible but non-competitive manner, unlike the more potent nicotinic antagonist tubocurarine (IC50 = 0.35 mu M) whose competitive blockade was overcome by a physostigmine-induced increase in acetylcholine. Serpentine up to 100 mu M did not change diaphragm contractions suggesting reduced affinity for neuromuscular nicotinic receptors. Despite strong in vitro AchE inhibition, serpentine failed to restore diaphragm contractions upon submaximal tubocurarine blockade, suggesting that poor tissue penetration may prevent serpentine from inhibiting AchE in deep neuromuscular synapses in the ex-vivo preparation. To our knowledge, the present study is the first to assess the effect of C. roseus root extracts, as well as of serpentine, ajmalicine and catharanthine on AchE. The results described herein suggest that the currently overlooked C roseus roots may constitute a promising source of compounds with pharmaceutical interest. Moreover, given serpentine's potent in vitro AchE inhibitory activity and low cholinergic receptor affinity, it is conceivable that minor structural modifications may yield a potent and selective AchE inhibitor, potentially useful for the pharmacological management of conditions such as Alzheimer's disease and/or myasthenia gravis. (C) 2009 Elsevier GmbH. All rights reserved.