Drugs, memory, and metamemory: A dose-effect study with lorazepam and scopolamine.

This experiment was designed to use the graded dose-related amnesia produced by the benzodiazepine lorazepam (1.0, 2.0 mg/70 kg, oral) and the anticholinergic scopolamine (0.3, 0.6 mg/70 kg, subcutaneous) as a tool to explore the cognitive and neurochemical mechanisms underlying metamemory in the judgment of learning paradigm, with a placebo-controlled independent groups design in healthy volunteers (n=12/group). Results provide evidence for a pharmacological dissociation between effects on memory versus metamemory (relative accuracy of item-by-item monitoring) across a range of levels of memory performance and suggest that the drugs selectively impair those aspects of metamnemonic monitoring that require participants' awareness of their overall current state of functioning (absolute accuracy of prospective item-by-item monitoring, prospective global monitoring) but not those that rely solely on assessment of individual item characteristics (relative accuracy of item-by-item monitoring). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Scopolamine impairs human recognition memory: Data and modeling.

Eight subjects studied a set of complex visual images after administration of 0.4 mg scopolamine. Another 8 subjects performed the same task without drug administration. On a subsequent item recognition test, subjects rated, on a 5-point scale, their confidence that the studied pictures and an equal number of unstudied lures were actually presented. Results showed that scopolamine affected responses to studied items, but not unstudied lures, demonstrating an unambiguous effect of scopolamine on recognition memory. To describe the scopolamine-injected subjects' data, the authors constructed a new model of 2-process recognition that includes the A. P. Yonelinas (1994) model as a limiting case. The model analysis suggests that scopolamine affected both familiarity and recollection. In particular, scopolamine did not affect the frequency with which recollection took place, but rather, affected the amount of recollected information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

鱿鱼卵磷脂对东莨菪碱痴呆小鼠学习记忆功能的影响

本文比较研究了鱿鱼卵磷脂和蛋黄磷脂对老年痴呆小鼠学习记忆能力的影响。雄性BALB/c小鼠分为正常对照、模型、鱿鱼卵磷组(SL)和蛋黄磷脂组(EL),喂养1周后,腹腔注射东莨菪碱造模并进行行为学测试。测定脑皮层、白质、海马中乙酰胆碱酯酶(Tch E)、超氧化物歧化酶(SOD)、单胺氧化酶(MAO)活力和脑内丙二醛(MDA)含量。结果显示,SL组水迷宫潜伏期显著降低,而穿越平台次数和目标象限停留时间显著提高,行为学改善效果优于EL组。SL能显著降低脑内各组织Tch E活力、MDA水平和白质中MAO活力,显著提高脑皮层、海马和白质中SOD活力,且作用效果优于EL。综上,鱿鱼卵磷脂通过影响中枢胆碱能神经系统和脑内抗氧化系统,改善了东莨菪碱所致痴呆小鼠学习记忆能力。     

托烷类生物碱的合成研究进展

托烷类生物碱是具有8氮杂双环[3,2,1]辛烷分子骨架的一类化合物。它们及其类似物在医疗上占有重要地位。就其代表物东莨菪碱、山莨菪碱和包公藤甲素以及重要中间体的合成方法进行综述。     

Risk assessment of buckwheat flour contaminated by thorn-apple (Datura stramonium L.) alkaloids: a case study from Slovenia

In Slovenia, a mass poisoning incident involving 73 consumers with symptoms such as dry mouth, hot red skin, blurred vision, tachycardia, urinary retention, ataxia, speech disturbance, disorientation and visual hallucinations occurred in 2003. In all cases, consumers had eaten buckwheat flour food products within the last few hours. Investigations by responsible authorities identified the contamination of a range of buckwheat food products with thorn-apple (Datura stramonium L.) seeds containing toxic alkaloids, atropine and scopolamine. To ensure the safe consumption of buckwheat food products, we carried out risk characterisation and proposed provisional maximum residue levels (MRLs) of atropine and scopolamine mixture in buckwheat flour. In the absence of critical “no observed adverse effect levels” for atropine and scopolamine, we based our estimation of the acute reference doses on the lowest recommended therapeutic doses. Taking into account the additive effect of the two alkaloids, we calculated acute reference doses of the mixture, that is 0.05?µg/kg of body mass for atropine and 0.03?µg/kg of body mass for scopolamine. MRLs for atropine and scopolamine mixture in buckwheat flour were estimated in a worst-case scenario, that is consumption of 100?g of flour by a child weighing 10?kg and taking into account a range of atropine/scopolamine ratio in implicated food products, that is 0.85–3.3. We proposed the national MRLs for atropine/scopolamine mixture in buckwheat food products: 4.0?µg/kg (atropine) and 2.0?µg/kg(scopolamine). However, in view of the large variability in the alkaloid content, depending on the origin of the Datura, we propose that risk assessment should be carried out on a case-by-case basis, taking into account the ratio between atropine and scopolamine content in a particular sample.     

侧脑室注射东莨菪碱对吗啡依赖大鼠戒断反应的抑制作用

目的 观察非选择性毒蕈碱(M)受体拮抗剂东莨菪碱、选择性M1 受体拮抗剂哌拉唑嗪以及选择性M2受体拮抗剂美索四氨对吗啡戒断反应的影响。方法 采用吗啡依赖大鼠模型侧脑室注射上述药物, 并用腹腔注射纳洛酮诱发戒断反应, 记录60 min 内戒断症状。结果 侧脑室注射东莨菪碱(25, 50 μg)、哌拉唑嗪(20 μg)和美索四氨(25 μg)可明显抑制由纳洛酮诱发戒断反应, 东莨菪碱减轻吗啡戒断症状呈明显量效关系。结论 侧脑室注射东莨菪碱能减轻吗啡戒断反应, 提示中枢胆碱能神经毒蕈碱(M)受体在吗啡依赖和耐受过程中起重要作用。     

Novel CFTR Activator Cact-3 Ameliorates Ocular Surface Dysfunctions in Scopolamine-Induced Dry Eye Mice

Cystic fibrosis transmembrane conductance regulator (CFTR) is highly expressed on the ocular epithelium and plays a pivotal role in the fluid secretion driven by chloride transport. Dry eye disease is one of the most common diseases with limited therapeutic options. In this study, a high-throughput screening was performed to identify novel CFTR activators capable of inducing chloride secretion on the ocular surface. The screening of 50,000 small molecules revealed three novel CFTR activators. Among them, the most potent CFTR activator, Cact-3 (7-(3,4-dimethoxyphenyl)-N-(4-ethoxyphenyl)pyrazolo [1,5-α]pyrimidine-2-carboxamide), produced large and sustained Cl⁻ currents in WT-CFTR-expressing FRT cells with no alterations of ANO1 and hERG channel activity. The application of Cact-3 strongly activated CFTR in the ocular epithelia of mice and it also significantly increased CFTR-mediated Cl⁻ transport in a primary cultured human conjunctival epithelium. Cact-3 strongly stimulated tear secretion in normal mice. In addition, Cact-3 significantly reduced ocular surface damage and the expression of proinflammatory factors, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in an experimental mouse model of dry eye disease. These results suggest that Cact-3, a novel CFTR activator, may be a potential development candidate for the treatment of dry eye disease.     

东莨菪碱及其大鼠体内代谢物的电

用液相色谱-电喷雾串联质谱(LC-ESI-MSn)法检测东莨菪碱及其大鼠粪样中的代谢物。收集灌胃50mg.kg-1东莨菪碱的大鼠粪样,水浸泡后,用乙酸乙酯萃取,采用LC-MS及LC-MSn等方法检测原药及其代谢物。与空白粪样及东莨菪碱比较,根据代谢物分子量的变化(ΔM)及其多级质谱数据,鉴定并阐述其结构。在服药后的大鼠粪样中发现8种代谢物,分别为莨菪品、N-去甲基莨菪品、N-去甲基脱水东莨菪碱、脱水东莨菪碱、N-去甲基东莨菪碱、羟基东莨菪碱、N-氧化羟基东莨菪碱以及托品酸等。这些代谢物的鉴定可用于该药物体内代谢途径的研究。     

液相色谱-串联质谱法同时测定畜肉中阿托品、山莨菪碱、东莨菪碱、普鲁卡因和利多卡因残留量

目的建立液相色谱-串联质谱法(liquid chromatography-tandem mass spectrometry,LC-MS/MS)同时定性和定量分析畜肉中的阿托品、山莨菪碱、东莨菪碱、普鲁卡因和利多卡因残留量的方法。方法样品用磷酸盐缓冲溶液超声提取,SPE小柱净化,经C18色谱柱以0.1%乙酸溶液和乙腈梯度洗脱,流速0.4 m L/min,柱温30℃,采用电喷雾离子源正离子模式,多反应监测(multiple reaction monitoring,MRM)进行检测。结果5种化合物在0.5~50μg/kg范围内线性关系良好,线性相关系数均在0.999以上。在0.5、1.5、5.0μg/kg 3个添加水平的回收率范围为83.2%~100.3%,5种化合物方法检出限均为0.5μg/kg。结论液相色谱串联质谱法可靠、灵敏、准确,可用于畜肉中阿托品、山莨菪碱、东莨菪碱、普鲁卡因和利多卡因残留同时定性和定量分析。     

Neuroprotective Effect of Cudrania tricuspidata Fruit Extracts on Scopolamine-Induced Learning and Memory Impairment

Cudrania tricuspidata has diverse biological activities, such as antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. This study investigated the protective effects of C. tricuspidata fruit extracts (CTFE) against scopolamine (SCO)-induced neuron impairment. The neuroprotective effects of CTFE on SCO-induced memory dysfunction were confirmed in mice using the Barnes maze test. The results showed that co-treatment of SCO and CTFE increased the stay time in the target zone compared with SCO treatment alone. Similarly, the results obtained by the fear conditioning test revealed that SCO-CTFE co-treatment induced the freezing action time under both the contextual fear condition and the cued fear condition compared with SCO treatment alone. Moreover, we showed that CTFE reduced the SCO-induced acetylcholinesterase (AChE) activity, thereby increasing the acetylcholine concentration in mice hippocampal tissues. Consistent with the improvement of memory and recognition function in vivo, our in vitro results showed that CTFE induced cAMP response element binding protein (CREB) and extracellular regulated kinase 1/2 (ERK1/2) activity in PC12 cells and reduced SCO-induced AChE activity. In addition, the microarray results of the hippocampal tissue support our data showing that CTFE affects gene expressions associated with neurogenesis and neuronal cell differentiation markers such as spp1 and klk6. Overall, CTFE exerts a neuroprotective effect via regulation of the CREB and ERK1/2 signaling pathways and could be a therapeutic candidate for neurodegenerative diseases.