Antiamnesic effect of stevioside in scopolamine-treated rats

The present study was undertaken to explore the potential of stevioside in memory dysfunction of rats. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) in animals. Morris water maze (MWM) test was employed to assess learning and memory. Brain acetylcholinestrase enzyme (AChE) activity was measured to assess the central cholinergic activity. The levels of brain thiobarbituric acid-reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess the degree of oxidative stress. Scopolamine administration induced significant impairment of learning and memory in rats, as indicated by a marked decrease in MWM performance. Scopolamine administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (increase in TBARS and decrease in GSH) levels. Pretreatment of stevioside (250 mg/kg dose orally) significantly reversed scopolamine-induced learning and memory deficits along with attenuation of scopolamine-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that stevioside exerts a memory-preservative effect in cognitive deficits of rats possibly through its multiple actions.     

Ameliorative Effect of a Selective Endothelin ETA Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

The present study was designed to investigate the efficacy of selective ET_A receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5^th to 8^th week of L-methionine treatment). On 52^nd day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ET_A receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.     

纳洛酮对血管性痴呆大鼠学习和记忆能力的影响

目的 研究纳洛酮对血管性痴呆大鼠空间学习和记忆能力减退的防治作用及作用机制。方法 将30只SD大鼠随机分为模型组、给药组和对照组各10只。结扎模型组和给药组大鼠双侧颈总动脉，以制作血管性痴呆模型。模型制作成功后，给药组腹腔注射纳洛酮，0.8 mg·kg^-1·d^-1；模型组腹腔注射等量0.9%氯化钠注射液。对照组大鼠给予假手术，不结扎双侧颈总动脉，腹腔注射等量0.9%氯化钠注射液。均连续给药7 d。8周后进行Morris水迷宫试验，观察3组大鼠隐匿平台逃避潜伏期、去平台后每分钟穿越平台所在位置的次数、恢复平台后从一固定点爬上平台所用的时间，并做病理学检查。结果 模型组大鼠隐匿平台逃避潜伏期［(21.26±741) s］明显长于对照组［(7.80±4.70) s］和给药组［(8.10±2.93) s］(均P＜0.01)，但对照组和给药组之间差异无显著性；去除平台后，模型组大鼠每分钟穿越平台所在位置的次数［(4.44±1.74)次］明显少于对照组［(8.45±1.19)次］和给药组［(8.00±1.17)次］(均P＜0.01)，对照组和给药组差异无显著性；恢复平台后3组大鼠从一固定点爬上平台所用的时间无明显差别；病理检查结果显示，模型组大鼠脑海马(CA)1区锥体细胞数［(43.68±17.29)个］较对照组［(124.51±14.18)个］和给药组［(113.36±13.15)个］明显减少(均P＜0.01)。结论 纳洛酮对血管性痴呆大鼠空间学习和记忆能力减退有明显的防治作用。其机制可能与纳洛酮抑制大鼠脑CA1区锥体细胞丢失和保护脑细胞作用有关。     

促红细胞生成素联合头部亚低温治疗新生儿脑损伤的评价

目的:探讨促红细胞生成素(EPO)联合头部亚低温治疗新生儿脑损伤(NBD)的疗效。方法:脑损伤新生儿86例随机分为治疗组46例和对照组40例。治疗组应用重组人促红细胞生成素(rhEPO)100 U/kg肌肉或静脉注射,每周3次,应用2周;治疗组同时采用FX-2000亚低温治疗仪(深圳)头部亚低温治疗持续72 h,亚低温治疗结束后自然复温。对照组按HIE治疗方案进行。对各组于生后7 d、14 d、21 d、28 d进行新生儿行为神经测定(NBNA),并对生后3个月、6个月智能发育评估(CDCC)及6个月的随访情况进行分析。结果:生后7 d、14 d、21 d、28 d时治疗组NBNA评分高于对照组(t分别为2.008、5.341、6.238、7.485,P均<0.05);治疗组3个月与6个月智力发育指数(MDI)、心理运动发育指数(PDI)均高于对照组(P<0.05)。结论:头部亚低温与EPO的联合治疗新生儿脑损伤短期和远期效果优于常规治疗。     

The Effects of Puerariae Flos on Stress-induced Deficits of Learning and Memory in Ovariectomized Female Rats

Puerariae flos (PF) is a traditional oriental medicinal plant and has clinically been prescribed for a long time. The purpose of the present study was to examine the effect of PF on repeated stress-induced alterations of learning and memory on a Morris water maze (MWM) test in ovariectomized (OVX) female rats. The changes in the reactivity of the cholinergic system were assessed by measuring the immunoreactive neurons of choline acetyltransferase (ChAT) in the hippocampus after behavioral testing. The female rats were randomly divided into four groups: the nonoperated and nonstressed group (normal), the sham-operated and stressed group (control), the ovariectomized and stressed group (OS), and the ovariectomized, stressed and PF treated group (OSF). Rats were exposed to immobilization stress (IMO) for 14 d (2 h/d), and PF (400 mg/kg, p.o.) was administered 30 min before IMO stress. Results showed that treatments with PF caused significant reversals of the stress-induced deficits in learning and memory on a spatial memory task, and also increased the ChAT immunoreactivities. In conclusion, administration of PF improved spatial learning and memory in OVX rats, and PF may be useful for the treatment of postmenopausal-related dementia.     

Effects of scopolamine on acquisition of passive avoidance

Summary Scopolamine was tested for effects on acquisition of a passive-avoidance problem. First mice were given four trials 24 hours apart on a step-off apparatus. Various dose levels of the drug were studied. For one group the drug was injected i.p. 20 minutes prior to each trial, in the other immediately after. Doses of 5.0 mg/kg and higher greatly interfered with the acquisition of the response, but only when injected prior to the trial. These results failed to indicate any direct effect of the drug on the learning process. The only time the drug affected the behavior was when the animal was under its influence at the time of testing.A second experiment was conducted in which mice were trained as before but pre-injection of 5.0 mg/kg of scopolamine was used. However, the mice were injected with the drug on only some of the trials. In all, six groups were studied, and their performance compared with a group that had received scopolamine on all trials and with one that received saline on all trials. When the data were examined for evidence of dissociation, it was clear that it was not present. Further analysis showed that animals which had learned, as indicated by their performance on the early trials conducted when they were not drugged, failed to show evidence of memory when given additional trials after being drugged. This outcome clearly indicated that a major effect of scopolamine was on the performance of the animal. Also, animals which had received 1 or 2 trials while drugged and given additional trials in the nondrugged state, showed a rapid increase in latency on succeeding trials equal that of animals which had not been drugged at all.These results, in light of other research, indicate that the effect of scopolamine on this type of learning task does not appear to be through a modification of the consolidation process.A preliminary report of Experiment I was made at the Southeastern Psychological Association Annual Meeting in Atlanta, Georgia, April, 1967. Supported by NIMH Grant No. MH 12770-01 to the senior author.     

Effects of diazepam and scopolamine on storage,retrieval and organizational processes in memory

The effects of intramuscular injections of diazepam (0.3 mg/kg) and scopolamine (8 g/kg) on memory processes and subjective moods were studied in 36 volunteers. Subjects (Ss) were tested in groups of four in a double blind procedure with treatments distributed according to a Latin square design. Lists of words were presented to Ss who were then tested with an immediate free recall test prior to drug administration. Following injection delayed free recall and recognition tests were given. Subsequently two sets of lists were presented separately and tested in the same fashion. Two of the lists in the last set were composed of words falling into distinct categories. Memory was additionally analyzed by testing immediate recall of digit sequences and employing a visual recognition test. Subjective moods were evaluated with a rating questionnaire.Both diazepam and scopolamine impaired memory functions although the action of the latter drug was more pronounced and prolonged. The deficit appeared to be in the storage process leaving retrieval processes unaffected. Scopolamine in addition interfered with organizational processes. Subjectively, scopolamine also produced a larger sedative effect than diazepam.     

银杏叶提取物对东莨菪碱所致大鼠空间工作记忆障碍的影响

目的探讨银杏叶提取物对东莨菪碱所致大鼠空间工作记忆障碍的影响。方法大鼠随机分成3组:正常组、东莨菪碱组和银杏叶治疗组。水迷宫试验,东莨菪碱组按0.4mg/kg腹腔注射,以后每天注射等体积生理盐水,连用6d。正常对照组每天注射与东莨菪碱等体积的生理盐水连用6d;银杏叶治疗组按10mg/kg腹腔注射,1次/d,连用6d。1周后进行Morris水迷宫试验,观察3组大鼠平台逃避潜伏期,并与实验后第1天比较。结果两次逃避潜伏期在正常组呈非常显著性差异(46.4±17.7,13.4±8.2,P<0.01)东莨菪碱组无统计学差异(23.6±14.3,18.1±9.8,P>0.05),银杏叶组呈显著性差异(27.9±14.3,9.0±3.8,P<0.05)。结论M-型胆碱能受体阻滞剂东莨菪碱能损害大鼠空间工作记忆,银杏叶提取物能改善这种损害,说明银杏叶提取物是通过影响胆碱能系统来发挥其促智作用的。     

Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory,psychomotor performance and mood

The effects on memory, psychomotor functions and mood of intramuscular scopolamine (0.3 mg, 0.6 mg) were compared with those of oral lorazepam (2 mg) and placebo. Thirty-six volunteers took part in a doubleblind, independent groups design. Subjects completed a battery of tests 1 and 3 h after drug administration. Both doses of scopolamine produced levels of sedation comparable to that produced by lorazepam. The time course of effects of scopolamine and lorazepam differed but the pattern of psychomotor impairments and amnestic effects produced was very similar. In terms of mood, lorazepam had an anxiolytic effect whereas scopolamine increased ratings of anxiety. Levels of sedation, indexed by either subjective ratings or motor retardation (tapping speed), were related more to psychomotor performance than to performance on memory tasks. The results suggest that benzodiazepines and scopolamine have similar amnestic and sedative effects and as such may not offer distinct models of memory dysfunction.     

Effects of ethylcholine aziridinium,scopolamine and morphine on learning behaviors in morris water maze

To assess the learning behaviors of the various chemicals, such as ethylcholine aziridinium (AF64A), scopolamine and morphine, the chemicals were administered into either rat or mice. And water maze tests were performed before and during drug administration. In AF64A-treated groups (3 nmol/each ventricle), the latencies to escape was significantly increased in both of the pretraining- and posttraining groups. In scopolamine-treatment (2 mg/kg, sc) to the pretrained group, the latency to escape was significantly shortened after the acute administration of scopolamine. However in subacute treatment group with scopolamine, the latency to escape was significantly increased. In morphine-treated groups (10 mg/kg, ip), the latency to escape was significantly increased after the acute administration. However in subacute treatmment with morphine, the latency to escape was not changed. The results indicate that each chemical induces the learning impairment. However the chemical-induced learning impairment may have different characteristics upon the exposed chemical. Also the results suggest that both the motivation and the retrieval of memory might be impaired by AF64A.     

Inhibitory Effects of Eucommia ulmoides Oliv. Bark on Scopolamine-Induced Learning and Memory Deficits in Mice

Eucommia ulmoides Oliv. Bark (EUE) is commonly used for the treatment of hypertension, rheumatoid arthritis, lumbago, and ischialgia as well as to promote longevity. In this study, we tested the effects of EUE aqueous extract in graded doses to protect and enhance cognition in scopolamine-induced learning and memory impairments in mice. EUE significantly improved the impairment of short-term or working memory induced by scopolamine in the Y-maze and significantly reversed learning and memory deficits in mice as measured by the passive avoidance and Morris water maze tests. One day after the last trial session of the Morris water maze test (probe trial session), EUE dramatically increased the latency time in the target quadrant in a dose-dependent manner. Furthermore, EUE significantly inhibited acetylcholinesterase (AChE) and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus and frontal cortex in a dose-dependent manner. EUE also markedly increased brain-derived neurotrophic factor (BDNF) and phosphorylation of cAMP element binding protein (CREB) in the hippocampus of scopolamine-induced mice. Based on these findings, we suggest that EUE may be useful for the treatment of cognitive deficits, and that the beneficial effects of EUE are mediated, in part, by cholinergic signaling enhancement and/or protection.     

A comparison of the effects of scopolamine and diazepam on working memory

Two drug models of memory dysfunction, namely the benzodiazepine and the cholinergic models, have emerged from the considerable number of studies which have examined drug effects on information processing. The reported impairments produced by administration of compounds from these two families appear to be more similar than dissimilar, and to date, direct comparisons on traditional memory tasks have failed to differentiate the models. This study compared the effects of diazepam and scopolamine on tasks associated with separable components of working memory. The results indicate that this model also fails to discriminate between the drug models; both compounds selectively impaired tasks associated with the central executive mechanism and failed to disrupt tasks associated with the articulatory loop or the visuospatial scratchpad.     

丁苯酞软胶囊对脑缺血痴呆大鼠记忆能力的影响

目的观察丁苯酞软胶囊(dl-3n-butylphthalide,NBP)对脑缺血(cerebral infarction,CI)大鼠学习记忆能力的影响。方法 SD大鼠随机分为正常组、假手术组、模型组、治疗组与对照组。采用自体血栓法制作CI痴呆(vascular dementia VD)模型。治疗组采用NBP灌胃,对照组采用尼莫地平治疗,给药时间30 d。模型组、假手术组和正常组均给予生理盐水灌胃。治疗后以Morris水迷宫检测其学习记忆行为能力,HE染色检测梗死灶周围组织形态学改变。结果 Morris水迷宫实验中,与正常组比较,模型组大鼠逃避潜伏期明显延长(P<0.05),平均探索次数显著减少(P<0.05);与模型组比较,治疗组、对照组大鼠逃避潜伏期明显缩短(P<0.05),平均探索次数显著增加(P<0.05)。光镜观察显示,与模型组相比,治疗组和对照组均可见海马CA1区神经元数目明显增多,变性坏死细胞减少。结论 NBP可以改善VD大鼠学习记忆能力,其机制可能与抑制CI区细胞凋亡,保护海马CA1区细胞有关。NBP对CI后神经细胞有明显保护作用。     

糖尿病并发症相关性氧化应激的实验研究

目的链脲佐菌素(STZ)诱导大鼠1型糖尿病模型的基础上,探讨糖尿病氧化应激指标的变化。方法采用一次性腹腔注射STZ的方法,监测不同时点大鼠的空腹血糖、体质量及血浆中的丙二醛(MDA)和超氧化物歧化酶(SOD)等指标,并对结果进行统计学处理。结果大鼠注射STZ 72h后血糖值达到成模标准,并逐渐出现糖尿病表现,观察7周,始终满足成模标准,未见转复。DM组大鼠肾脏及肝脏肥大指数较CON组显著增加。氧化应激相关指标测定表明,较对照组相比,实验组大鼠血浆中脂质过氧化产物MDA水平显著升高,而SOD水平显著下降。结论本实验Ⅰ型糖尿病模型大鼠造模成功且模型稳定,氧化应激指标改变。     

Effects of scopolamine,trimipramine and diazepam on explicit memory and repetition priming in healthy volunteers

The effects of scopolamine, an anticholinergic drug, of trimipramine, a tricyclic antidepressant with both anticholinergic and sedative properties, of diazepam and a placebo, on explicit memory and repetition priming were assessed using a free-recall task and a word-stem completion task. Forty-eight healthy volunteers took part in this double-blind study. Diazepam provoked a dissociation between free recall, which was profoundly impaired, and word completion, which was spared. No significant changes in memory performances were observed in the scopolamine group; however, a significant correlation between explicit and implicit memory performances was observed in this group. At the low dose used, the effects of trimipramine on memory were mild. The results suggest that the cholinergic system is involved in the priming effect.     

Memory enhancing and neuroprotective effects of selected ginsenosides

The effects of ginsenosides Rg3(R), Rg3(S) and Rg5/Rk1 (a mixture of Rg5 and Rk1, 1:1, w/w), which are components isolated from processed Panax ginseng C.A. Meyer (Araliaceae), on memory dysfunction were examined in mice using a passive avoidance test. The ginsenosides Rg3(R), Rg3(S) or Rg5/Rk1, when orally administered for 4 days, significantly ameliorated the memory impairment induced by the single oral administration of ethanol. The memory impairment induced by the intraperitoneal injection of scopolamine was also significantly recovered by ginsenosides Rg3(S) and Rg5/Rk1. Among the three ginsenosides tested in this study, Rg5/Rk1 enhanced the memory function of mice most effectively in both the ethanoland scopolamine-induced amnesia models. Moreover, the latency period of the Rg5/Rk1-treated mice was 1.2 times longer than that of the control (no amnesia) group in both models, implying that Rg5/Rk1 may also exert beneficial effects in the normal brain. We also evaluated the effects of these ginsenosides on the excitotoxic and oxidative stress-induced neuronal cell damage in primary cultured rat cortical cells. The excitotoxicity induced by glutamate or N-methyl-D-aspartate (NMDA) was dramatically inhibited by the three ginsenosides. Rg3(S) and Rg5/Rk1 exhibited a more potent inhibition of excitotoxicity than did Rg3(R). In contrast, these ginsenosides were all ineffective against the H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal damage. Taken together, these results indicate that ginsenosides Rg3(S) and Rg5/Rk1 significantly reversed the memory dysfunction induced by ethanol or scopolamine, and their neuroprotective actions against excitotoxicity may be attributed to their memory enhancing effects.     

Effects of scopolamine on learning and memory in monkeys

The effects of scopolamine were evaluated in monkeys responding under operant procedures designed to evaluate drug effects on learning and memory. In one procedure, responding was maintained by food presentation under a multiple schedule. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-key responses changed each session (learning). In the other component, the discriminative stimuli for responses were the same each session (performance). In both components of the multiple schedule, scopolamine produced dose-related decreases in responding; there was little evidence of differential rate-decreasing effects between components. Percent errors in learning were increased in a dose-related manner, whereas percent errors in performance were generally unaffected except at high doses, which also produced substantial decreases in response rate. These results suggest that acquisition is more sensitive to the disruptive effects of scopolamine than is performance. The second procedure utilized repeated acquisition and delayed performance as a technique to study the effects of scopolamine on memory. In this procedure, each session was divided into three phases: acquisition, delay and performance. After a 24-h delay, scopolamine had little or no effect on retention, accuracy or rate of responding. In contrast, after a 60-min delay, scopolamine decreased retention in a dose-related manner. These data suggest that scopolamine produces a greater disruptive effect on short (60-min) versus long (24-h) delays.     

重组人促红细胞生成素对卵巢癌细胞EPOR表达及肿瘤增殖的影响

目的通过检测卵巢癌细胞中的促红细胞生成素受体（EPOR）表达，以及r—HuEPO对卵巢癌细胞增值的影响，探讨r—HuEPO在癌性贫血治疗中的意义。方法RT—PCR方法检测人卵巢癌细胞株HO-8910EPOR mRNA的表达及卵巢癌细胞增值影响。结果卵巢癌细胞表面有EPOR的表达。r—HuEPO干预后卵巢癌细胞增值受到抑制（P〈0．01）。结论EPOR在卵巢癌细胞株HO8910有表达，r—HuEPO可抑制卵巢癌细胞的增值发生，提示r—HuEPO可用于卵巢癌伴发的贫血的治疗。     

Effects of acute doses of oxiracetam in the scopolamine model of human amnesia

The scopolamine model of amnesia has been used to test the pharmacodynamic efficacy of oxiracetam in 12 healthy volunteers. The subjects were divided into four experimental groups, according to a double-blind cross over incomplete randomized block design. After a baseline neuropsychological examination, each subject received in two separate sessions one of the following treatments, as acute oral doses: oxiracetam 800, 1600, 2400 mg or placebo. One hour after treatment scopolamine hydrobromide (0.5 mg) was given subcutaneously. The cognitive performance was tested before and 1, 2, 3 and 25 h after scopolamine administration. Scopolamine caused a deterioration of performance of verbal episodic memory, semantic memory and attention tests. In comparison to placebo, oxiracetam improved the overall test performance, with a statistically significant difference at the dose of 1600 mg on delayed recall of word lists, and showed dose-related antagonism of scopolamine-induced effects also on semantic memory and attention. The efficacy of an acute dose of oxiracetam in reducing scopolamine-induced cognitive impairment supports the potential usefulness of this pharmacological model of amnesia for studying the effects of cognition enhancers in humans.     

克糖特对链脲霉素致糖尿病小鼠的降血糖作用及机制探讨

目的研究克糖特对链脲霉素致糖尿病(DM)小鼠的降血糖作用并初步探讨其机制。方法小鼠腹腔注射链脲霉素(STZ)150mg/kg建立DM模型,将建模成功的小鼠随机分为5组。格列本脲组:格列本脲50/(kg·d)灌胃(i.g.),克糖特高、中、低剂量[i.g.克糖特分别相当于生药50g/(kg·d),25g/(kg·d),12.5 g/(kg·d)];DM模型组:等容积生理盐水i.g.;与空白对照组:等容积生理盐水i.g.;均连续给药15d。并在相应时间采血测定空腹血糖(FBG)、胰岛素、三酰甘油(TG)、总胆固醇(TC)、血清肌酐(Cr)、尿酸(UA)等指标。结果克糖特有明显的降血糖作用,其作用呈剂量依赖性,并提高胰岛素水平;同时能不同程度地降低血清Cr、UA(P<0.01);血脂中的(TG)水平有降低趋势。结论克糖特能降低链脲霉素所致DM小鼠的血糖,增加胰岛素的分泌,对DM尤其并发症的治疗有潜在的应用价值。其降血糖作用机制可能与促进胰岛素分泌有关。