药学学报

Alkaloid	Effect	Target
Rhynchophylline	① Improving scopolamine and mecamylamine induced cognitive impairment^[3] ② Improving long-term potentiation in APP/PS1 mice^[6] ③ Protective effects against β-amyloid^[7-10] ④ Protective effects against glutamate induced excitability^[11] ⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15] ⑥ Protective effects against kainic acid induced epilepsy^[16] ⑦ Reducing amphetamine induced conditioned place preference[22, 26] ⑧ Protecting brain injury in subarachnoid hemorrhage^[27] and ischemic^[28] animal model	① Inhibiting the current of NMDA receptor^[12] ② Reducing muscarinic receptor- and 5-HT₂ receptor-mediated current responses in a competitive manner^[36] ③ Functionally turns delayed rectifiers into A-type K⁺ channels^[38] ④ Blockade of EphA4 signaling^[6] ⑤ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]
Isorhynchophylline	① Improving scopolamine induced cognitive impairment^[3] ② Improving β-amyloid^[4] and D-galactose^[5] induced cognitive impairment ③ Protective effects against β-amyloid^[7-10] ④ Protective effects against glutamate induced excitability^[11] ⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15] ⑥ Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ⑦ Enhancing autophagy in neuron^[32] ⑧ Reducing the immobility time in both forced swimming and tail suspension tests^[33]	① Inhibiting the current of NMDA receptor^[12] ② Reducing muscarinic receptor- and 5-HT₂ receptor-mediated current responses in a competitive manner^{[36, 37]} ③ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]
Corynoxine	① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ② Enhancing autophagy in neuron^[30]
Corynoxine B	① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ② Enhancing autophagy in neuron^[31]	① Blocking SNCA-HMGB1 interaction^[31]

Alkaloid	Effect	Target
Rhynchophylline	① Improving scopolamine and mecamylamine induced cognitive impairment^[3] ② Improving long-term potentiation in APP/PS1 mice^[6] ③ Protective effects against β-amyloid^[7-10] ④ Protective effects against glutamate induced excitability^[11] ⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15] ⑥ Protective effects against kainic acid induced epilepsy^[16] ⑦ Reducing amphetamine induced conditioned place preference[22, 26] ⑧ Protecting brain injury in subarachnoid hemorrhage^[27] and ischemic^[28] animal model	① Inhibiting the current of NMDA receptor^[12] ② Reducing muscarinic receptor- and 5-HT₂ receptor-mediated current responses in a competitive manner^[36] ③ Functionally turns delayed rectifiers into A-type K⁺ channels^[38] ④ Blockade of EphA4 signaling^[6] ⑤ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]
Isorhynchophylline	① Improving scopolamine induced cognitive impairment^[3] ② Improving β-amyloid^[4] and D-galactose^[5] induced cognitive impairment ③ Protective effects against β-amyloid^[7-10] ④ Protective effects against glutamate induced excitability^[11] ⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15] ⑥ Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ⑦ Enhancing autophagy in neuron^[32] ⑧ Reducing the immobility time in both forced swimming and tail suspension tests^[33]	① Inhibiting the current of NMDA receptor^[12] ② Reducing muscarinic receptor- and 5-HT₂ receptor-mediated current responses in a competitive manner^{[36, 37]} ③ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]
Corynoxine	① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ② Enhancing autophagy in neuron^[30]
Corynoxine B	① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ② Enhancing autophagy in neuron^[31]	① Blocking SNCA-HMGB1 interaction^[31]

钩藤碱及其同分异构体对神经系统作用的研究进展

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黄晏 ¹ , 周文霞 ¹^,^* , 张永祥 ¹ , 赵勤实 ²

药学学报 | 专题报道·中药药理与神经疾患 2018,53(7): 1017-1022

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药学学报 | 专题报道·中药药理与神经疾患 2018, 53(7): 1017-1022

钩藤碱及其同分异构体对神经系统作用的研究进展

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黄晏¹, 周文霞¹^,^*, 张永祥¹, 赵勤实²

作者信息

1.军事科学院军事医学研究院毒物药物研究所, 抗毒药物与毒理学国家重点实验室, 北京 100850

2.中国科学院昆明植物研究所, 植物化学与西部植物资源持续利用国家重点实验室, 云南昆明 650201

通讯作者:

* 周文霞, Tel:86-10-66931625, Fax:86-10-68211656, E-mail:zhouwx@nic.bmi.ac.cn

Research progresses in pharmacological effects of rhynchophylline and its isomers on nervous system

Yan HUANG¹, Wen-xia ZHOU¹^,^*, Yong-xiang ZHANG¹, Qin-shi ZHAO²

Affiliations

1. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China

2. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China

出版时间: 2018-07-12 doi: 10.16438/j.0513-4870.2018-0250

文章导航

摘要

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钩藤是我国常用的中药之一，具有清热平肝，息风定惊之功效。生物碱类物质是钩藤的主要活性物质，现代实验药理学研究表明钩藤及其生物碱类物质对神经系统具有广泛的生物学效应，其中钩藤碱是钩藤中含量最高、研究最多的生物碱。本文就钩藤碱及其同分异构体(异钩藤碱、柯诺辛碱和柯诺辛碱B)对神经系统的作用及机制进行综述，为其应用拓展和深入研究提供参考。

关键词

钩藤 / 钩藤碱 / 柯诺辛碱 / 神经系统 / 阿尔茨海默病 / 癫痫

Abstract

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Uncaria rhynchophylla is one of the frequently used herbs in China, it is mainly used for heat-clearance, suppression of hyperactive liver, calming endogenous wind and arresting convulsion in traditional Chinese medicine (TCM). Alkaloids are the main active materials in Uncaria rhynchophylla, pharmacological studies have shown that Uncaria rhynchophylla and its alkaloids have comprehensive biological effects on the nervous system. Rhynchophylline is one of the most abundant alkaloids in Uncaria rhynchophylla. The recent studies demonstrate that rhynchophylline and its isomers (isorhynchophylline, corynoxine, corynoxine B) may be good drug candidates for treatment of Alzheimer's disease, Parkinson's disease, epilepsy, etc. Although the structures of the 4 alkaloids are very similar, they have different effects on nervous system. For example, corynoxine and corynoxine B exhibit better sedative effects than isorhynchophylline. Rhynchophylline and isorhynchophylline have been extensively studied. For development and utilization of rhynchophylline for nervous system disease, more studies are needed to unveil the structure-function relationship and the underlying mechanisms. Here, we summarizes the progresses the effects of rhynchophylline and its isomers on the nervous system.

Key words

Uncaria rhynchophylla / rhynchophylline / corynoxine / nervous system / Alzheimer's disease / epilepsy

引用本文

黄晏, 周文霞, 张永祥, 赵勤实. 钩藤碱及其同分异构体对神经系统作用的研究进展. 药学学报, 2018 , 53 (7) : 1017 -1022 . DOI: 10.16438/j.0513-4870.2018-0250

Yan HUANG, Wen-xia ZHOU, Yong-xiang ZHANG, Qin-shi ZHAO. Research progresses in pharmacological effects of rhynchophylline and its isomers on nervous system[J]. Acta Pharmaceutica Sinica, 2018 , 53 (7) : 1017 -1022 . DOI: 10.16438/j.0513-4870.2018-0250

正文

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茜草科(Rubiaceae)钩藤(Uncaria)属常绿藤本植物有40余种, 其中钩藤(Uncaria rhynchophylla)、大叶钩藤(Uncaria macrophylla)、毛钩藤(Uncaria hirsuta)、华钩藤(Uncaria sinensis)和无柄果钩藤(Uncaria sessilifructus)为我国药典收录的药用植物, 以带钩的茎枝入药, 具有清热平肝、息风定惊的功效。吲哚生物碱是钩藤中重要的活性物质, 其主要含有钩藤碱(rhynchophylline)、异钩藤碱(isorhynchophylline)、去氢钩藤碱(corynoxeine)、异去氢钩藤碱(isocorynoxeine)、柯诺辛碱(corynoxine)、柯诺辛碱B (corynoxine B)、毛钩藤碱(hirsutine)、去氢毛钩藤碱(hirsuteine)和缝籽嗪甲醚(geissoschizine methyl ether, GM)等(图 1)。其中钩藤碱、异钩藤碱、柯诺辛碱和柯诺辛碱互为同分异构体。钩藤(Uncaria rhynchophylla)中钩藤碱和异钩藤碱含量最高, 分别占其总生物碱的28.9%和14.7%^[1]。目前, 国内对钩藤碱和异钩藤碱的研究较多, 国外对缝籽嗪甲醚的报道较多。本文主要就钩藤碱及其同分异构体(异钩藤碱、柯诺辛碱和柯诺辛碱B)对神经系统的作用和机制进行综述, 为钩藤和钩藤碱在神经系统疾病中的应用和进一步深入研究开发提供参考。

1 阿尔茨海默病

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随着老龄化社会的加剧, 阿尔茨海默病(Alzheimer's disease, AD)日益成为危害老年人身心健康和生活质量的主要疾病之一。AD作为一个多因素复杂疾病, 其发病机制十分复杂。目前, β淀粉样蛋白(amyloid-beta, Aβ)的过度沉积、tau蛋白的过度磷酸化、胆碱能系统功能降低、兴奋性损伤、炎性损伤和氧化应激等均被认为与AD有着密切关系。钩藤及其活性物质对AD的作用已有大量研究报道, 钩藤对AD的作用研究进展已有文献综述^[2]。本文主要综述近年来钩藤碱及其同分异构体对AD的作用研究。

钩藤碱和异钩藤碱可改善多种AD相关模型动物的学习记忆能力和神经突触可塑性损伤。胆碱能系统功能降低是导致AD学习记忆能力损伤的主要原因之一, 增强胆碱系统功能也是目前临床使用的抗AD药物的重要机制之一。腹腔注射钩藤碱和异钩藤碱(10和20 mg·kg^-1)均可明显改善乙酰胆碱M型受体拮抗剂东莨菪碱(scopolamine, 3 mg·kg^-1, ip)所致的ddY小鼠学习记忆(跳台)损伤, 钩藤碱(20 mg·kg^-1)可改善乙酰胆碱N型受体拮抗剂美加明(mecamylamine, 15 mg·kg^-1, ip)所致的学习记忆(跳台)损伤^[3]。Aβ沉积被认为是AD发病最重要的病理因素之一, 侧脑室注射Aβ是常用的AD模型之一。连续灌胃给予异钩藤碱(20~40 mg·kg^-1) 21天, 对Aβ侧脑室注射所致的大鼠学习记忆障碍具有明显的改善作用, 并能降低Aβ所致的tau蛋白磷酸化水平升高^[4]。此外, 在D-半乳糖所致的小鼠衰老模型上, 灌胃给予异钩藤碱(20~40 mg·kg^-1) 8周, 也可明显改善D-半乳糖所致的空间学习记忆障碍^[5]。突触可塑性被认为是学习记忆的神经生物学基础, 长时程增强(long-term potentiation, LTP)是突触可塑性的主要功能指标之一, 灌胃给予钩藤碱(50 mg·kg^-1, 4周)可明显改善APP/PS1转基因小鼠(5月龄)海马LTP的降低^[6]。关于柯诺辛碱和柯诺辛碱B对学习记忆及神经突触可塑性的影响尚未见报道。

在细胞水平上, 钩藤碱和异钩藤碱具有对抗Aβ诱导的细胞毒性反应, 降低兴奋性毒性和脂多糖(lipopolysaccharide, LPS)诱导的神经炎性反应等作用。异钩藤碱10 μmol·L^-1便可明显改善Aβ所致的PC12细胞活性降低, 而钩藤碱需要在100 μmol·L^-1才有明显的改善作用, 提示异钩藤碱抗Aβ毒性的作用要强于钩藤碱^[7-10]。柯诺辛碱和柯诺辛碱B以及去氢钩藤碱、异去氢钩藤碱则对Aβ所致的神经毒性没有明显的保护作用^[8]。在对抗谷氨酸诱导的兴奋性损伤方面, 异钩藤碱的作用也比钩藤碱强, 异钩藤碱0.1 mmol·L^-1即可明显改善谷氨酸诱导的原代培养神经元活性降低, 而钩藤碱则需要在1 mmol·L^-1才具有明显的作用^[11]。膜片钳实验表明, 钩藤碱(IC₅₀ = 43.2 μmol·L^-1)和异钩藤碱(IC₅₀ = 48.3 μmol·L^-1)也具有N-甲基天冬氨酸(N-methylaspartate, NMDA)受体拮抗作用^[12]。此外, 钩藤碱和异钩藤碱还能抑制LPS诱导的小胶质细胞炎性反应^[13-15]。

综上, 钩藤碱及异钩藤碱对AD相关模型动物的学习记忆具有明显的改善作用, 并可对抗Aβ的神经毒性、兴奋性毒性及炎性损伤等与AD密切相关的病理损伤因素。现有研究表明, 异钩藤碱对抗AD的作用可能要强于钩藤碱。柯诺辛碱和柯诺辛碱B对AD的作用研究很少。目前对钩藤碱、异钩藤碱、柯诺辛碱和柯诺辛碱B对AD的作用尚需系统深入地研究, 以便深入认识其作用和机制及更好的开发利用。

2 癫痫

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癫痫(epilepsy)俗称“羊角风”或“羊癫风”, 是大脑神经元突发性异常放电, 导致短暂的大脑功能障碍的一种慢性疾病。据《中国药典(2015版)》所载, 钩藤具有息风定惊、清热平肝之功效。用于肝风内动、惊痫抽搐、高热惊厥、感冒夹惊、小儿惊啼、妊娠子痫和头疼眩晕。所以, 抗惊厥和癫痫是钩藤的重要药理作用。现代药理学研究也表明, 钩藤中的生物碱类成分具有抗癫痫作用, 其中以对钩藤碱和异钩藤碱的研究为主。

目前认为, 中枢神经系统的兴奋性异常增强是导致癫痫或惊厥的主要原因之一。作为中枢神经系统主要的兴奋性神经递质, 谷氨酸被认为与癫痫或惊厥发生密切相关。腹腔注射钩藤碱(0.25 mg·kg^-1) 3天, 对海人藻酸(谷氨酸受体亚型海人藻酸受体的激动剂)腹腔注射诱导的大鼠癫痫具有明显的抑制作用, 并对模型动物脑组织的氧化应激水平、JNK磷酸化及NF-κB激活具有明显改善作用^[16], 可降低模型动物脑组织中的IL-1β和升高脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)的水平^[17]。在细胞水平的研究发现, 钩藤碱(1 μmol·L^-1)和异钩藤碱(0.1~1 μmol·L^-1)可明显对抗谷氨酸所致的原代培养神经活性降低^[11]。钩藤碱和异钩藤碱对抗谷氨酸毒性的作用可能与其钙拮抗^{[11, 18]}和NMDA受体拮抗作用相关^{[12, 19]}。

3 镇静

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有研究表明, 在100 mg·kg^-1 (ig)剂量下, 异钩藤碱、柯诺辛碱和柯诺辛碱B均可延长硫喷妥钠诱导的ICR小鼠睡眠时间, 而钩藤碱则没有明显的作用^[20]; 柯诺辛碱和柯诺辛碱B在30 mg·kg^-1即可明显抑制ICR小鼠的自主活动, 而异钩藤碱在100 mg·kg^-1剂量下才有上述作用^[21]。其镇静作用可能与调节多巴胺系统有关, 异钩藤碱(60 mg·kg^-1)、柯诺辛碱(30、60 mg·kg^-1)和柯诺辛碱B (30、60 mg·kg^-1)均可明显抑制多巴胺释放增强剂甲基苯丙胺(methamphetamine)诱导的活动性增加; 针对多巴胺受体激动剂阿扑吗啡(apomorphine)诱导的活动性增加, 异钩藤碱(60、100 mg·kg^-1)和柯诺辛碱B (30、100 mg·kg^-1)均有明显抑制作用, 柯诺辛碱(100 mg·kg^-1)则没有明显的作用^[21]。以上结果提示, 柯诺辛碱和柯诺辛碱B的镇静作用强于异钩藤碱, 而钩藤碱似乎无类似作用; 在作用机制方面, 异钩藤碱和柯诺辛碱B的镇静作用可能与其拮抗多巴胺受体的作用有关, 柯诺辛碱则可能是通过抑制多巴胺释放发挥作用。

不同的钩藤生物碱具有不同强度的镇静作用, 这决定了不同种的钩藤镇静作用的强弱。研究表明, 大叶钩藤含量最高的生物碱是柯诺辛碱B和异钩藤碱^[21], 钩藤含量最高的生物碱是钩藤碱和异钩藤碱^[1], 华钩藤中含量最高的是缝籽嗪甲醚和去氢毛钩藤碱^[21]; 在生物效应方面, 大叶钩藤吲哚总碱0.5 g·kg^-1即可明显抑制自主活动, 华钩藤吲哚总碱2 g·kg^-1才具有明显的作用, 而钩藤吲哚总碱在2 g·kg^-1对自主活动没有明显影响^[21]。

4 神经系统的其他作用

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钩藤碱可以降低甲基苯丙胺诱导的条件位置偏爱(conditioned place preference, CPP), 并可纠正甲基苯丙胺诱导的脑内神经递质紊乱(谷氨酸、多巴胺、去甲肾上腺素升高; γ-氨基丁酸、乙酰胆碱、内啡肽降低)^[22]和降低甲基苯丙胺诱导的中前额叶皮层和海马CA1区的GluN2B表达的升高^{[23, 24]}; 在斑马鱼的实验中也得到了类似的结果, 钩藤碱可减少甲基苯丙胺诱导的斑马鱼位置偏爱行为和降低GluN2B的表达^{[25, 26]}。

在蛛网膜下腔出血模型中, 造模后立即腹腔注射钩藤碱(10 mg·kg^-1)可明显抑制模型动物的脑水肿和脑组织中的氧化应激水平^[27]; 在脑卒中模型(permanent middle cerebral artery occlusion, pMCAO)中, 钩藤碱可以改善模型动物的脑组织水肿和梗死体积, 并可激活PI3K/Akt/mTOR通路和抑制TLRs/ NF-kappaB通路, PI3K抑制剂(wortmannin)可阻断钩藤碱的保护作用^[28], 提示钩藤碱保护脑缺血可能是通过调节Akt/mTOR通路实现。

钩藤提取物可以减少阿扑吗啡诱导的6-羟多巴胺(6-OHDA)单侧纹状体注射模型旋转运动和改善模型动物黑质多巴胺神经元的减少, 并对6-OHDA诱导的PC12细胞凋亡和氧化应激反应具有改善作用^[29]; 异钩藤碱、柯诺辛碱和柯诺辛碱B对多种神经细胞系(N2a、SH-SY5Y和PC12)和原代培养神经元的自噬具有增强作用, 并可促进α-突触素(α-synuclein)的清除^[30-32], 提示其对帕金森病可能具有潜在的治疗作用。

异钩藤碱还具有潜在的抗抑郁作用, 灌胃给予异钩藤碱(10~40 mg·kg^-1) 7天, 可使动物在强迫游泳和悬尾实验中的不动时间明显减少^[33]。

钩藤总碱可明显降低蛙坐骨神经的动作电位, 提示其具有神经阻滞作用, 而钩藤碱则没有明显的神经阻滞作用^[34], 目前钩藤总碱中神经阻滞作用的物质基础尚不明确。

5 作用靶点

收起

钩藤碱和异钩藤碱对多种离子通道均具有抑制作用。钩藤碱(EC₅₀ = 43.2 μmol·L^-1)和异钩藤碱(EC₅₀ = 48.3 μmol·L^-1)可以浓度依赖性(1~100 μmol·L^-1)降低NMDA受体介导的电流, 对α-氨基羟甲基恶唑丙酸(α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid, AMPA)受体和代谢型谷氨酸受体1和5 (mGlu 1/5)介导的电流没有影响; 与MK801等离子通道开放阻断剂不同的是, 膜电位对钩藤碱和异钩藤碱的抑制作用没有明显影响, 提示其不是离子通道开放阻断剂; 钩藤碱和异钩藤碱对NMDA和甘氨酸诱发NMDA电流的最大效应(the maximal response)具有明显抑制作用, 但对效价(IC₅₀)没有明显影响, 提示其不是谷氨酸和甘氨酸结合位点的拮抗剂^{[12, 19, 35]}, 以上结果提示钩藤碱和异钩藤碱可能是通过变构调节NMDA受体, 进而抑制谷氨酸和甘氨酸与NMDA受体结合实现其拮抗NMDA受体的作用, 其具体作用位点尚需进一步研究。此外, 钩藤碱和异钩藤碱可以竞争性地抑制5-羟色胺(5-hydroxytryptamine, 5-HT) 2型受体(5-HT₂)和乙酰胆碱M受体介导的电流^{[36, 37]}; 钩藤碱能功能性地使延迟整流型钾通道转变为A型钾通道^[38]。

Eph (erythropoietin producing human hepatocellular)受体家族是受体酪氨酸激酶(RTKs)家族成员中最大的亚族, 其A4亚型(EphA4)在神经发育和神经突触可塑性中有重要作用^[39]。EphA4可通过移除膜表面的AMPA受体调节突触可塑性^[40], APP/PS1小鼠脑组织中EphA4表达明显升高, 抑制EphA4可明显改善APP/PS1小鼠的LTP^[6]。Fu等^[6]通过分子对接虚拟筛选实验表明, 钩藤碱可以与EphA4特异性结合(-9.0 kcal·mol^-1), 其结合势能明显低于其已有特异性拮抗剂Cpd1 (-6.5 kcal·mol^-1); Pulldown实验显示钩藤碱可与EphA4的胞外段特异性结合; 在APP/PS1小鼠上, 钩藤碱可以明显下调EphA4相关信号通路和改善LTP, 提示钩藤碱是EphA4的特异性抑制剂。

SNCA是编码α-synuclein的基因, 其与HMGB1 (high mobility group box 1)结合后抑制HMGB1在胞内转位, 抑制HMGB1与BECN1的结合进而抑制自噬; 免疫共沉淀(co-IP)实验表明, 柯诺辛碱B可降低SNCA与HMGB1的结合, 并对自噬功能具有明显的促进作用^[31], 提示柯诺辛碱B能通过抑制SNCA与HMGB1的结合恢复SNCA诱导的自噬功能降低。

此外, 钩藤碱和异钩藤碱可与选择性α₁肾上腺素(α_1A)受体阻断剂坦索罗辛(tamsulosin)竞争性结合肾上腺素α_1A受体^[41], 对α_1A受体功能的影响尚需进一步研究。

6 结语

收起

综上, 钩藤碱及其同分异构体对中枢神经系统具有广泛的药理作用(表 1)。已有研究结果提示, 钩藤碱及其同分异构体对AD的研究相对比较系统, 具有潜在的开发价值, 抗癫痫、镇静等方面的作用比较明确, 对其他神经系统疾病的作用研究相对较少; 研究对象主要集中在钩藤碱, 其同分异构体异钩藤碱, 特别是柯诺辛碱和柯诺辛碱B的研究更少。因此, 有必要更系统深入地研究钩藤碱及其同分异构体的作用及机制, 并对其构效关系进行系统分析, 对开发利用钩藤及其生物碱类物质具有重要意义。

基金

收起

国家科技重大新药创制专项资助项目(2016ZX09J16104-001)

参考文献

收起

文献

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2018年第53卷第7期

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doi: 10.16438/j.0513-4870.2018-0250

接收时间：2018-03-22
首发时间：2026-01-15
出版时间：2018-07-12

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收稿日期：2018-03-22
修回日期：2018-04-17

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国家科技重大新药创制专项资助项目(2016ZX09J16104-001)

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1.军事科学院军事医学研究院毒物药物研究所, 抗毒药物与毒理学国家重点实验室, 北京 100850

2.中国科学院昆明植物研究所, 植物化学与西部植物资源持续利用国家重点实验室, 云南昆明 650201

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* 周文霞, Tel:86-10-66931625, Fax:86-10-68211656, E-mail:zhouwx@nic.bmi.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Alkaloid	Effect	Target
Rhynchophylline	① Improving scopolamine and mecamylamine induced cognitive impairment^[3] ② Improving long-term potentiation in APP/PS1 mice^[6] ③ Protective effects against β-amyloid^[7-10] ④ Protective effects against glutamate induced excitability^[11] ⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15] ⑥ Protective effects against kainic acid induced epilepsy^[16] ⑦ Reducing amphetamine induced conditioned place preference[22, 26] ⑧ Protecting brain injury in subarachnoid hemorrhage^[27] and ischemic^[28] animal model	① Inhibiting the current of NMDA receptor^[12] ② Reducing muscarinic receptor- and 5-HT₂ receptor-mediated current responses in a competitive manner^[36] ③ Functionally turns delayed rectifiers into A-type K⁺ channels^[38] ④ Blockade of EphA4 signaling^[6] ⑤ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]
Isorhynchophylline	① Improving scopolamine induced cognitive impairment^[3] ② Improving β-amyloid^[4] and D-galactose^[5] induced cognitive impairment ③ Protective effects against β-amyloid^[7-10] ④ Protective effects against glutamate induced excitability^[11] ⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15] ⑥ Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ⑦ Enhancing autophagy in neuron^[32] ⑧ Reducing the immobility time in both forced swimming and tail suspension tests^[33]	① Inhibiting the current of NMDA receptor^[12] ② Reducing muscarinic receptor- and 5-HT₂ receptor-mediated current responses in a competitive manner^{[36, 37]} ③ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]
Corynoxine	① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ② Enhancing autophagy in neuron^[30]
Corynoxine B	① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice ② Enhancing autophagy in neuron^[31]	① Blocking SNCA-HMGB1 interaction^[31]

Alkaloid

Effect

Target

Rhynchophylline

① Improving scopolamine and mecamylamine induced cognitive impairment^[3]
② Improving long-term potentiation in APP/PS1 mice^[6]
③ Protective effects against β-amyloid^[7-10]
④ Protective effects against glutamate induced excitability^[11]
⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15]
⑥ Protective effects against kainic acid induced epilepsy^[16]
⑦ Reducing amphetamine induced conditioned place preference[22, 26]
⑧ Protecting brain injury in subarachnoid hemorrhage^[27] and ischemic^[28] animal model

① Inhibiting the current of NMDA receptor^[12]
② Reducing muscarinic receptor- and 5-HT₂
receptor-mediated current responses in a competitive manner^[36] ③ Functionally turns delayed rectifiers into A-type K⁺ channels^[38]
④ Blockade of EphA4 signaling^[6]
⑤ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]

Isorhynchophylline

① Improving scopolamine induced cognitive impairment^[3]
② Improving β-amyloid^[4] and D-galactose^[5] induced cognitive impairment
③ Protective effects against β-amyloid^[7-10]
④ Protective effects against glutamate induced excitability^[11]
⑤ Protective effects against lipopolysaccharide induced inflammatory reaction in microglia^[13-15]
⑥ Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice
⑦ Enhancing autophagy in neuron^[32]
⑧ Reducing the immobility time in both forced swimming and tail suspension tests^[33]

① Inhibiting the current of NMDA receptor^[12]
② Reducing muscarinic receptor- and 5-HT₂
receptor-mediated current responses in a competitive manner^{[36, 37]} ③ Competitive binding with a_1A adrenergic receptors in a manner similar to tamsulosin^[41]

Corynoxine

① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice
② Enhancing autophagy in neuron^[30]

Corynoxine B

① Prolonging the time of thiopental-induced hypnosis^[20] and inhibiting locomotion^[21] in ICR mice
② Enhancing autophagy in neuron^[31]

① Blocking SNCA-HMGB1 interaction^[31]