Scopolamine model of dementia: electroencephalogram findings and cognitive performance

Background

Memory and cognitive functions are known to decline with advancing age. Studies have suggested that this may be due to a decrease in cholinergic function in the brains of elderly people. This review aims to assess studies documented in the literature dealing with the ‘scopolamine model’ of dementia.

Methods

Sources included MedLine searches from the last 10 years (search for ‘scopolamine model’, ‘dementia’, ‘electroencephalogram’, ‘cognition’) and references from original and review articles. The aim was to include human and animal studies occupying the cholinergic hypothesis in cognitive dysfunction. Electroencephalographic (EEG) and cognition findings were considered.

Results

Scopolamine influences delta, theta, alpha and beta activity in EEG and partially mimics the EEG changes found in patients with senile dementia or dementia of the Alzheimer type. Effects on different cognitive functions have been extensively documented.

Conclusion

Scopolamine produces similar memory deficits seen in the elderly, but the drug cannot induce the full range of deficits seen in patients with Alzheimer's disease. Various aspects of memory were unaffected by scopolamine administration. Memory improvements in elderly subjects can be achieved after cholinergic stimulation.

     

Tremulous jaw movements in rats:a model of parkinsonian tremor

Several pharmacological and neurochemical conditions in rats induce ‘vacuous' or ‘tremulous' jaw movements. Although the clinical significance of these movements has been a subject of some debate, considerable evidence indicates that the non-directed, chewing-like movements induced by cholinomimetics, dopamine antagonists and dopamine depletions have many of the characteristics of parkinsonian tremor. These movements occur within the 3–7 Hz peak frequency range that is characteristic of parkinsonian tremor. Tremulous jaw movements are induced by many of the conditions that are associated with parkinsonism, and suppressed by several different antiparkinsonian drugs, including scopolamine, benztropine, -DOPA, apomorphine, bromocriptine, amantadine and clozapine. Striatal cholinergic and dopaminergic mechanisms are involved in the generation of tremulous jaw movements, and substantia nigra pars reticulata appears to be a major basal ganglia output region through which the jaw movements are regulated. Future research on the neurochemical and anatomical characteristics of tremulous jaw movements could yield important insights into the brain mechanisms that generate tremulous movements.     

Effects of physostigmine on scopolamine–induced changes in quantitative electroencephalogram and cognitive performance

The effects of physostigmine on scopolamine-induced changes were investigated in a randomized, double-blind cross-over study utilizing quantitative electroencephalogram (qEEG) and cognitive tasks. Ten healthy male volunteers received scopolamine 0·6 mg subcutaneously. After 90 min, single doses of either 0·5, 1·0 and 2·0 mg physostigmine salicylate or placebo were administered subcutaneously in randomized order. qEEG, cognitive function and the visual analogue scale were recorded before and at 1, 2, 3, 4, 6, and 8 h after scopolamine administration; that was 0·5, 1·5, 2·5, 4·5, and 6·5 h after physostigmine administration. Scopolamine produced an increase in delta (1·25–4·50 Hz) and theta power (4·75–6·75 Hz) in qEEG 1 h after administration compared to baseline, while physostigmine decreased the spectral delta power density in qEEG compared to placebo. The maximal effect of physostigmine was seen up to 1·5 h after injection. A dose-dependent reversal of the scopolamine induced decrements in cognitive performance was found 0·5 h after administration of physostigmine. Psychometric tests sensitively discriminated between the doses of physostigmine, and showed dose- and time-dependent effects. The results suggest that physostigmine may reverse the scopolamine-induced changes in both qEEG and cognitive function. This reversal was temporary and of short duration. © 1998 John Wiley & Sons, Ltd.     

EEG correlates of acute nicotinic and muscarinic cholinergic blockade: separate and combined administration of mecamylamine and scopolamine in normal human subjects

Anticholinergic drugs have been proposed as a possible acute model for human electroencephalographic (EEG) studies focused on dementia but the interactive effects of muscarinic and nicotinic cholinergic receptor system blockade on the regulation of electrocortical activity has yet to be examined. EEG recordings were carried out in 15 normal subjects before and after the double-blind acute administration of a placebo, a centrally acting nicotinic blocker (20 mg of mecamylamine), a centrally acting muscarinic blocker (0·6 mg of scopolamine) and a combination dose of mecamylamine and scopolamine. Mecamylamine decreased absolute and relative beta power and increased relative theta power. Scopolamine increased relative power in both theta and beta frequency bands. Mecamylamine produced greater theta increments than scopolamine, while combined administration of the two central blockers induced changes similar to that observed with mecamylamine administered alone. Results are discussed in relation to electrocerebral activity in normal and pathological aging. © 1997 John Wiley & Sons, Ltd.     

基于体内药效学结合网络药理学的百合地黄汤抗老年痴呆的机制研究

目的 基于体内药效学结合网络药理学对百合地黄汤治疗老年痴呆的机制进行研究。方法 将清洁级ICR雄性小鼠按体重随机分为6组：正常组、模型组、咯利普兰组、百合地黄汤低、中、高剂量组。连续给药十四天,通过行为学试验来验证百合地黄汤对东莨菪碱诱导的AD模型小鼠行为学变化及药物的改善作用。最后通过呕吐试验来验证百合地黄汤产生呕吐不良反应的程度。通过中药成分数据库 TCMSP、GeneCards、OMIM、DRUGBANK 数据库分别收集百合、地黄化学成分、成分及疾病相关靶点,两者取交集后,运用 STRING 数据库分析靶点蛋白的相互作用,利用Metascape数据库进行生物功能和通路分析,相关结果采用 Cytoscape 3.8.0 进行构图和网络拓扑结构分析,并在此基础上进行机制研究。结果 动物试验结果显示AD小鼠与空白组有显著差异,说明造模成功;百合地黄汤可以逆转AD小鼠的行为学表现,作用与咯利普兰相当。在呕吐试验中,咯利普兰组麻醉苏醒时间显著延长,百合地黄汤组无明显影响,说明其没有呕吐的不良反应。网络药理学中共收集到9个活性成分,54个关键靶点,对接结果显示前10个核心靶点都表现为良好的对接结果。其中对接结果显示其作用与PRKACA、PTGS2密切相关,在此基础上进行了小鼠海马cAMP、PKA、p-CREB和BDNF检测,发现百合地黄汤能纠正东莨菪碱诱导的cAMP-PKA-CREB-BDNF通路下调,作用与阳性药相当,验证了网络药理学的结果。结论 本研究将百合地黄汤对东莨菪碱诱导的AD小鼠模型的抗老年痴呆药效学研究与网络药理学分析结合,预测药物可能通过影响cAMP,上调PTGS2基因的表达以及调控cAMP-PKA-CREB-BDNF信号通路来产生抗老年痴呆作用,为百合地黄汤的临床开发利用提供基础。     

均匀设计法优选痹痛宁贴剂的处方基质配比

目的优选痹痛宁贴剂的处方基质配比,对其体外透皮吸收行为进行考察。方法采用U6(66)均匀设计安排试验,利用改良Franz扩散池进行离体皮肤体外渗透实验。以东莨菪碱和乌头碱24h累积渗透量为指标优选处方配比。结果基质比例分别为PVA11.02%、PVP29.93%、甘油7.42%、氮酮4.95%、丙二醇11.06%,贴剂具有最大的累积释药量,释药曲线符合Higuchi方程。结论采用均匀设计法优选的配方组成符合骨架控释型透皮给药系统的要求。     

石杉碱甲改善老年大鼠水迷宫操作记忆障碍(英文)

目的:测试石杉碱甲对自然衰老及东莨菪碱导致的空间记忆缺损的作用。方法:采用大鼠的水迷宫操作,检测石杉碱甲对获得及记忆的作用。结果:连续7天获得试验期间,皮下注射石杉碱甲0.1-0.2mg/kg能明显缩短老年大鼠找到平台的潜伏期。在第8天撤去平台的记忆测试,石杉碱甲0.1,0.2与0.4 mg/kg明显延长老年大鼠在该平台区的游泳时间。单次腹腔注射东莨菪碱0.1mg/kg明显损害已训练达标老年大鼠的空间记忆。皮下注射石杉碱甲0.4 mg/kg明显翻转东莨菪碱产生的记忆损害作用。结论:石杉碱甲能改善老年大鼠自然衰老或东莨菪碱产生的记忆障碍。     

组胺H_3受体拮抗剂clobenpropit对大鼠放射状迷宫程序空间记忆的作用(英文)

目的:研究中枢组胺H_3受体拮抗剂clobenpropit{S-[3-(4(5)-咪唑基)-丙基-N-(4-氯苄基)]异硫脲,VUF9153}对东莨菪碱引起的大鼠空间记忆障碍的作用.方法:采用8-方向放射状迷宫的程序研究大鼠的空间记忆,并利用高效液相法测定脑内组胺含量.结果:侧脑室内注射clobenpmpit(50μg)可明显对抗东莨菪碱导致的空间记忆障碍.相反,组胺H_3受体激动剂(R)-α-甲基组胺(5,10μg)可明显抑制clobenpropit的空间记忆改善作用.另外,clobenpropit的作用被α-氟甲基组胺酸(10,20μg)有效地抑制.结论:中枢组胺H_3受体与大鼠空间记忆的调节密切相关,而且其作用与胆碱能神经相关.     

Χ－硒化卡拉胶对小鼠空间分辨学习的影响

用Ｙ型迷宫箱测试小鼠空间分辨能力，结果：ｐｏ　－硒化卡拉胶（　－ｓｅｌｅｎｏｃａｒｒａｇｅｅ－ｎａｎ，　－ＳｅＣ）１８０ｍｇ／ｋｇ及１０８ｍｇ／ｋｇ（ｑｄ×１４ｄ）能增强正常小鼠的学习能力，提高学习成绩；ｐｏ　－ＳｅＣ１８０、１０８及６４ｍｇ／ｋｇ（ｑｄ×１４）对东莨菪碱（ｉｐ４ｍｇ／ｋｇ）所致小鼠学习障碍均有拮抗作用；ｐｏ　－ＳｅＣ１８０ｍｇ／ｋｇ（ｑｄ×１４）对东莨菪碱（ｉｐ５ｍｇ／ｋｇ）所致小鼠记忆保持障碍有改善作用。以上表明　－ＳｅＣ对脑的学习功能有促进作用，并能拮抗药物引起的学习与记忆功能的损害，改善大脑功能．     

银杏叶提取物改善小鼠记忆作用的研究

银杏叶醇提取物及水提取物均能明显改善小鼠由NaNO₂及东莨菪碱引起的记忆损害。醇提取物的作用较水提物强,且对正常成年小鼠亦有促进记忆保持的作用。二种提取物均能延长大剂量NaNO₂注射后小鼠的存活时间。