The cognition-enhancing activity of E1R,a novel positive allosteric modulator of sigma-1 receptors

Background and Purpose

Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors.

Experimental Approach

E1R was tested for sigma receptor binding activity in a [³H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca²⁺ concentration ([Ca²⁺]_i) assays and in an electrically stimulated rat vas deferens model. E1R''s effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion.

Key Results

Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084''s stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca²⁺]_i increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity.

Conclusion and Implications

E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases.     

The effects of scopolamine on the recall of repeated words: a preliminary investigation

We investigated the effects of scopolamine on the recall of repeated words. Subjects performed continuous recognition memory tasks both before and after the administration of scopolamine, and were asked to recall as many words from the lists as they could immediately after the recognition tasks. Cerebral blood flow was measured by H₂¹⁵O positron emission tomography during the performance of each task. Scopolamine altered performance on the recall task such that subjects were just as likely to recall words presented once as they were to recall words presented three times. In addition, scopolamine decreased cerebral blood flow during the performance of the task. The extent to which scopolamine decreased cerebral blood flow appeared to be associated with the change in performance on the recall task.     

长托宁用于心脏病人非心脏手术前用药的临床研究

[目的]探讨长托宁作为心脏病人非心脏手术前用药的临床效果。[方法]ASAⅡ-Ⅲ级的稿人50例,随机分为长托宁组和东莨菪碱组,免用术前药,入室后肌注长托宁0．01mg／kg和东莨菪碱0．006mg／kg,40min后开始麻醉和手术。记录给药前、给药后10、20、30、40min时的心率（HR）、血压（Bp）变化情况及观察病人镇静、口干程度。[结果]Ⅰ组SBP在给药后30、40min时低于给药前;DBP在20、30、40min时较给药前低;HR在20、30min时较给药前低,（P〈0．05）。Ⅱ组SBP、DBP在给药后30min时均较用药前高,且明显高于I组,（P〈0．05）。HR在20、30、40min时高于给药前,且较Ⅰ组明显增快,（P〈0．05）。组间比较口干与镇静程度均没有显著差异。[结论]长托宁作为心脏病人非心脏手术前用药较东莨菪碱效果好。     

Procyanidins extracted from the lotus seedpod ameliorate scopolamine‐induced memory impairment in mice

The major purpose of this study was to determine the effect of procyanidins extracted from the lotus seedpod (LSPC) on the learning and memory impairments induced by scopolamine (1 mg/kg, i.p.) in mice. The capacities of memory and learning were evaluated by the Morris water maze and the step‐down avoidance test. LSPC (50, 100, 150 mg/kg BW, p.o.) significantly reversed scopolamine‐induced learning and memory impairments in the Morris water maze test, as evaluated by shortened escape latency and swimming distance. In the step‐down avoidance test, LSPC (50, 100, 150 mg/kg BW, p.o.) treatment significantly reduced the number of errors and shortened latency compared with that of scopolamine. In addition, LSPC was also found to inhibit acetyl cholinesterase (AChE) activity. These results of this study suggest that LSPC may play a useful role in the treatment of cognitive impairment caused by AD and aging. Copyright © 2009 John Wiley & Sons, Ltd.     

HPLC法测定天仙子东莨菪碱和莨菪碱的含量

目的建立天仙子药材中东莨菪碱和莨菪碱的高效液相测定方法。方法采用Symmetrix ODS-H色谱柱,以乙腈-0.1%三氟乙酸水(14∶86)为流动相,检测波长210nm,流速1.0mL/min,测定天仙子药材中东莨菪碱和莨菪碱的含量。结果氢溴酸东莨菪碱和硫酸阿托品的线性范围分别为4.02~513.64μg/mL(r=0.999 9)和4.00~512.00μg/mL(r=0.999 8),平均回收率分别为98.41%和98.79%。结论 HPLC法测定准确、可控,能快速、简便地控制天仙子药材的质量。     

Neuroprotection of N-benzylcinnamide on scopolamine-induced cholinergic dysfunction in human SH-SY5Y neuroblastoma cells

Alzheimer's disease, a progressive neurodegenerative disease, affects learning and memory resulting from cholinergic dysfunction. Scopolamine has been employed to induce Alzheimer's disease-like pathology in vivo and in vitro through alteration of cholinergic system. N-benzylcinnamide(PT-3), purified from Piper submultinerve, has been shown to exhibit neuroprotective properties against amyloid-β-induced neuronal toxicity in rat cortical primary cell culture and to improve spatial learning and memory of aged rats through alleviating oxidative stress. We proposed a hypothesis that PT3 has a neuroprotective effect against scopolamine-induced cholinergic dysfunction. PT-3(125–200 n M) pretreatment was performed in human neuroblastoma SH-SY5 Y cell line following scopolamine induction. PT-3(125–200 n M) inhibited scopolamine(2 m M)-induced generation of reactive oxygen species, cellular apoptosis, upregulation of acetylcholinesterase activity, downregulation of choline acetyltransferase level, and activation of p38 and JNK signalling pathways. These findings revealed the underlying mechanisms of scopolamine-induced Alzheimer's disease-like cellular dysfunctions, which provide evidence for developing drugs for the treatment of this debilitating disease.     

HPLC法测定苯巴比妥东莨菪碱片含量的测量不确定度评价

评价了HPLC法测定苯巴比妥东莨菪碱片含量的测量不确定度。通过不确定度来源分析，建立不确定度的数学模型，并考察测定中的各影响因素。氢溴酸东莨菪碱、苯巴比妥的扩展不确定度分别为2．1％、1．5％，含量测定结果可表示为（108．6±2．1）％、（108．3±1．5）％。     

二氧化碳超临界流体萃取洋金花中东莨菪葳的研究

 目的：对二氧化碳超临界流体(C0₂-SFE)萃取洋金花中东莨菪碱进行研究，确立最佳萃取条件。方法：采用二氧化碳超临界流体萃取法，在温度4℃、压力34.924X10³Pa下，以0.1ml氨水作碱化剂、0.2ml甲醇作夹带剂、二氧化碳静态萃取5 min、动态萃取5 ml,并用反相离子对HPLC对东莨菪碱定量。结果：所得样品萃取完全且含较少杂质，反相离子对HPLC专一、重现性好，加样回收率为98.7S%，RSD=2.33%,日内及日间变异分别为0.95%和0.86%。结论：此法简便快速、无环境污染，为洋金花质量控制提供了可行的分析手段。     

东莨菪碱和毒扁豆碱对吗啡处理大鼠Morris水迷宫空间学习能力的影响

目的:研究吗啡及胆碱能系统的药物对大鼠空间学习能力的影响 方法:应用Morris水迷宫学习程序研究吗啡处理大鼠的空间学习能力及其在东莨菪碱和毒扁豆碱作用下的变化.结果:高剂量吗啡(10mg/kg)和低剂量吗啡(3mg/kg)对大鼠学习能力的影响差异有显著性;东莨菪碱(3mg/kg)和吗啡(10mg/kg)联合给药,可以使吗啡时学习能力的损害进一步加重;毒扁豆碱(0.1mg/kg)可以改善吗啡所致的学习能力损害,但不能完全逆转.结论:吗啡损害大鼠空间学习能力,已存在量-效关系;胆碱能系统与吗啡处理大鼠空间学习能力关系密切,有可能影响成瘾的发生及治疗.     

HPLC法同时测定咳喘清滴丸中盐酸麻黄碱、盐酸伪麻黄碱、氢溴酸东莨菪碱的含量

目的建立咳喘清滴丸中盐酸麻黄碱、盐酸伪麻黄碱、氢溴酸东莨菪碱的含量测定方法。方法采用HPLC法,色谱柱为Eclipse XDB C8(150 mm×4.6 mm,5μm),流动相为甲醇0.02 mol.L-1磷酸二氢钾溶液0.03 mol.L-1磷酸溶液(体积比为5.0∶47.5∶47.5),流速为1.0 mL.min-1,检测波长为210 nm。结果对照品盐酸麻黄碱、盐酸伪麻黄碱、氢溴酸东莨菪碱分别在21~210、20~200、5~50 ng内与色谱峰面积呈良好的线性关系,其相关系数均为r=0.999 9,平均加样回收率分别为100.84%、100.39%、97.86%,RSD分别为1.45%、1.43%、1.51%(n=5)。结论测定方法可作为咳喘清滴丸质量控制方法。