Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse Models of Dementia

The present study was undertaken to explore the potential of erythropoietin in memory deficits of mice. Memory impairment was produced by scopolamine (0.5 mg/kg, i.p.) and intracerebroventricular streptozotocin (i.c.v STZ, 3 mg/kg, 10 µl, 1^st and 3^rd day) in separate groups of animals. Morris water-maze test was employed to assess learning and memory. The levels of brain thio-barbituric acid reactive species (TBARS) and reduced glutathione (GSH) were estimated to assess degree of oxidative stress. Brain acetylcholinesterase enzyme (AChE) activity was also measured. Scopolamine/streptozotocin administration induced significant impairment of learning and memory in mice as indicated by marked decrease in Morris water-maze performance. Scopolamine/streptozotocin administration also produced a significant enhancement of brain AChE activity and brain oxidative stress (an increase in TBARS and a decrease in GSH) levels. Treatment of erythropoietin (500 and 1,000 IU/Kg i.p.) significantly reversed scopolamine- as well as streptozotocin-induced learning and memory deficits along with attenuation of those-induced rise in brain AChE activity and brain oxidative stress levels. It may be concluded that erythropoietin exerts a beneficial effect in memory deficits of mice possibly through its multiple actions including potential anti-oxidative effect.     

Long-term feeding effects of stevioside sweetener on some toxicological parameters of growing male rats

Several attempts to decrease sugar demand by introducing stevioside as a sugar substitute in children's food products have been made, but safety issues were concerned. This exploratory study investigated the effects of stevioside low dose (SL), high dose (SH) and low dose with inulin (SL + I) for 12 weeks on the body weight, organ relative weight, hematological and biochemical parameters and enzyme activities of young male rats. The SL dose used in this study was 15 mg kg^?1 per day and the SH dose was 100‐fold the low dose. Enormous similarities in most parameters were observed with no significant differences between SL, SL + I and control except in the lipid profile. Total lipid reduction in SL and SL + I and significant high‐density lipoprotein increase in SL + I were observed, which may be considered as clinically beneficial. Significant decreases in serum tartrate‐resistant acid phosphatase activity were also observed in all treatments. Treatment with SH caused significant changes in all investigated toxicological parameters. The results indicated that, although the SL dose was higher than the stevioside temporary accepted daily intake (5.0 mg kg^?1 body weight), no toxicological effects were observed in SL or SL + I on body weight, organ relative weight, hematological and biochemical parameters or enzyme activities investigated in this study, whereas stevioside high dose (1500 mg kg^?1 per day) may be considered as a toxic dose for the same biological parameters in young male rats. However, the effects of SL, SH and SL + I on serum tartrate‐resistant acid phosphatase activity need more investigation. Copyright © 2010 John Wiley & Sons, Ltd.     

东莨菪碱和毒扁豆碱对吗啡训练大鼠空间学习的影响

目的 :研究吗啡训练大鼠的空间学习障碍与胆碱能系统的关系。方法 :ip吗啡和其他药品 ;通过Morris水迷宫任务检测药物对吗啡训练大鼠空间学习的影响。结果 :10mg·kg- 1 的吗啡对大鼠学习空间任务具有显著的抑制作用 ;10mg·kg- 1 吗啡和 3mg·kg- 1 东莨菪碱联合给药 ,对大鼠学习空间任务的损害更加严重 ;0 .1mg·kg- 1 毒扁豆碱能够降低 10mg·kg- 1 吗啡对大鼠空间学习的影响。结论 :吗啡对学习空间任务的影响机制之一是通过降低胆碱能系统的功能水平实现的     

A double-blind placebo-controlled study of the effectiveness and tolerability of oral stevioside in human hypertension

AIMS: Stevioside is a natural plant glycoside isolated from the plant Stevia rebaudiana which has been commercialized as a sweetener in Japan for more than 20 years. Previous animal studies have shown that stevioside has an antihypertensive effect. This study was to designed to evaluate the effect of stevioside in human hypertension. METHODS: A multicentre, randomized, double-blind, placebo-controlled study was undertaken. This study group consisted of 106 Chinese hypertensive subjects with diastolic blood pressure between 95 and 110 mmHg and ages ranging from 28 to 75 years with 60 subjects (men 34, women 26; mean +/- s.d., 54.1+/-3.8 years) allocated to active treatment and 46 (men 19, women 27; mean +/- s.d., 53.7+/-4.1 years) to placebo treatment. Each subject was given capsules containing stevioside (250 mg) or placebo thrice daily and followed-up at monthly intervals for 1 year. RESULTS: After 3 months, the systolic and diastolic blood pressure of the stevioside group decreased significantly (systolic: 166.0+/-9.4-152.6+/-6.8 mmHg; diastolic: 104.7 +/- 5.2-90.3+/-3.6 mmHg, P<0.05), and the effect persisted during the whole year. Blood biochemistry parameters including lipid and glucose showed no significant changes. No significant adverse effect was observed and quality of life assessment showed no deterioration. CONCLUSIONS: This study shows that oral stevioside is a well tolerated and effective modality that may be considered as an alternative or supplementary therapy for patients with hypertension.     

康寿灵对东莨菪碱痴呆模型大鼠学习记忆的保护作用

目的：观察康寿灵对东莨菪碱诱导的记忆障碍大鼠学习记忆的影响，并探讨其可能的作用机制。方法：各组大鼠分别用生理盐水（正常对照组、模型组）、康寿灵（低、中、高剂量组）和石杉碱甲（阳性对照组）灌胃37d。第31天起进行Morris水迷宫行为测试，连续7d。行为测试结束后，进行大鼠脑组织丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）及ATPase活性测定。结果：预先给予大鼠康寿灵30d可改善东莨菪碱导致的记忆障碍，使大鼠脑组织中抗氧化酶SOD、GSH-Px及ATPase活性升高，而MDA含量降低。结论：康寿灵对东莨菪碱引起的大鼠学习记忆能力障碍有明显保护作用，其作用机制可能与抗氧化作用密切相关。     

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.     

反相高效液相法测定甜叶菊中莱鲍迪苷A和甜菊糖苷的含量

目的建立反相高效液相色谱法（RP．HPLC）测定甜叶菊中莱鲍迪苷A（RA）和甜菊糖苷（ST）的含量。方法采用welchMaterials XB—C18柱（250mm×4．6mm,5μm）,以乙腈．10mmol·L^-1磷酸酸钠缓冲液（pH=2．67,35：65,v～）为流动相,流速0．7mL·min^-1,检测波长210nm,柱温30℃,进样量5此。结果以外标法定量,RA和sT均在O．25～2．50mg·mL^-1与峰面积线性关系良好,r〉0．9995。RA回收率为100．3％,RSD为2．3％（n=6）,ST回收率为101．0％,RSD为2．5％（n=6）。结论本方法快捷、准确、可靠,易操作,可用于甜叶菊及相关产品中RA和ST含量测定。     

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.     

Antidepressant and anxiolytic activity of Lavandula officinalis aerial parts hydroalcoholic extract in scopolamine-treated rats

Context: Anxiety and depression are common in Alzheimer’s disease (AD). Despite some evidence, it is difficult to confirm Lavandula officinalis Chaix ex Vill (Lamiaceae) as an anxiolytic and antidepressant drug.

Objective: The effects of L. officinalis extract were studied in scopolamine-induced memory impairment, anxiety and depression-like behaviour.

Materials and methods: Male NMRI rats were divided into control, scopolamine alone-treated group received scopolamine (0.1?mg/kg) intraperitoneally (i.p.), daily and 30?min prior to performing behavioural testing on test day, for 12 continuous days and extract pretreated groups received aerial parts hydro alcoholic extract (i.p.) (100, 200 and 400?mg/kg), 30?min before each scopolamine injection. Memory impairment was assessed by Y-maze task, while, elevated plus maze and forced swimming test were used to measure anxiolytic and antidepressive-like activity.

Results: Spontaneous alternation percentage in Y maze is reduced by scopolamine (36.42?±?2.60) (p?≤?0.001), whereas lavender (200 and 400?mg/kg) enhanced it (83.12?±?5.20 and 95?±?11.08, respectively) (p?≤?0.05). Also, lavender pretreatment in 200 and 400?mg/kg enhanced time spent on the open arms (15.4?±?3.37 and 32.1?±?3.46, respectively) (p?≤?0.001). On the contrary, while immobility time was enhanced by scopolamine (296?±?4.70), 100, 200 and 400?mg/kg lavender reduced it (193.88?±?22.42, 73.3?±?8.25 and 35.2?±?4.22, respectively) in a dose-dependent manner (p?≤?0.001).

Discussion and conclusion: Lavender extracts improved scopolamine-induced memory impairment and also reduced anxiety and depression-like behaviour in a dose-dependent manner.     

Protective effect of Cnestis ferruginea and its active constituent on scopolamine-induced memory impairment in mice: A behavioral and biochemical study

Abstract

Context: Cnestis ferruginea Vahl ex DC (Connaraceae) (CF) is used in traditional African medicine in the management of CNS disorders. The degeneration and dysfunction of cholinergic neurons is closely associated with the cognitive deficits of Alzheimer’s disease (AD) and oxidative stress has been implicated in its pathogenesis. However, the influence of C. ferruginea on the cholinergic system and oxidative stress parameters has not been explored.

Objective: The present study investigates the effect of methanol root extract of C. ferruginea and its active constituent amentoflavone (CF-2) on memory, oxidative stress and acetylcholinesterase (AChE) activity in scopolamine-induced amnesia.

Materials and methods: Mice were orally treated with CF (25–200?mg/kg), CF-2 (6.25–25?mg/kg) for three days and memory impairment was induced by intraperitoneal injection of scopolamine (3?mg/kg). Memory function was evaluated by passive avoidance and Morris water maze tests. Biochemical parameters of oxidative stress and cholinergic function were estimated in brain after the completion of behavioral studies.

Results: Scopolamine caused memory impairment along with increased AChE activity and oxidative stress in mice brain. Oral administration of CF and CF-2 significantly prevented scopolamine-induced memory impairment, inhibited AChE and enhanced antioxidant enzyme activity in the brain following scopolamine injection as compared to vehicle administration in scopolamine (i.p.)-treated mice that were comparable to the effect of tacrine.

Discussion and conclusion: The study demonstrated that C. ferruginea and its constituent have significant protective effect against scopolamine-induced memory deficits in mice that can be attributed to their antioxidant and antiAChE activity.     

Antiamnesic effect of cytoflavin and neuronol in rats with ischemic impairment of cerebral circulation

The antiamnesic action of the new complex preparations cytoflavin and neuronol was studied in rats with a cerebral ischemia model, tested for the passive avoidance conditioned reflex. The neuroprotector effect of drugs was determined by morphological methods. Both cytoflavin and neuronol reduced neuronal damage in the pyramidal layer of the hippocampus and prevented the development of amnesia during the entire period of cerebral ischemia (3-21 days). Both drugs also improved horizontal locomotor activity and emotional reactions of animals in the open field test.     

川芎嗪对大鼠脑损伤后保护作用的研究

目的探讨川芎嗪对大鼠脑损伤后的保护作用。方法将60只大鼠随机分为对照组、损伤组及治疗组,每组20只。损伤组、治疗组以改良Feeney自由落体脑损伤模型方式对大鼠制作脑损伤动物模型,治疗组大鼠在脑损伤后接受川芎嗪治疗。实验第14天应用HE染色、电镜观察及水迷宫实验评价脑损伤对大鼠形态学和学习记忆的影响及川芎嗪的保护作用。结果 HE染色结果显示,应用川芎嗪注射液治疗后,治疗组正常运动神经元数目多于损伤组;电镜下可见治疗组神经细胞核固缩程度、染色质浓染程度、胞浆空泡化较损伤组减轻。水迷宫实验结果显示,治疗组第1次穿过平台时间较损伤组缩短[(7.68±1.09)s vs.(10.15±2.35)s],在靶象限活动时间较损伤组延长[(86.14±16.68)s vs.(62.38±19.67)s],穿过平台次数多于损伤组(6.4±2.3vs.3.8±1.6),差异均有统计学意义。结论川芎嗪治疗可能在脑组织损伤及大鼠学习记忆功能中发挥重要的治疗效应。     

Antiamnesic effects of D-pipecolic acid and analogues of Pro-Leu-Gly-NH2 in rats

The antiamnesic effects of prolyl-leucyl-glycinamide (PLG) and analogues of this tripeptide were investigated in rats. Retrograde amnesia was induced by electroconvulsive shock treatment and the degree of amnesia was characterized by the attenuation of one-trial learning passive avoidance response. PLG resulted in dose-dependent attenuation of retrograde amnesia. Structural modifications included N-terminal protection, substitution of the C-terminal NH2 group, replacement of the N-terminal amino acid, and replacement of the second amino acid of the tripeptide. Some tripeptides, all of them containing D-pipecolic acid instead of the N-terminal proline, were more effective than PLG. Therefore, D-pipecolic acid, D-pipecolamide and their N-terminally protected analogues were also investigated, and were found to have powerful antiamnesic effects.     

Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-month-old) and old (8- to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP(3)) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP(3) concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.     

Effects of 5-HT6 receptor antagonism and cholinesterase inhibition in models of cognitive impairment in the rat

Background and purpose:

The beneficial effect of 5-HT₆ receptor antagonism in cognition remains controversial. This study has been undertaken to reassess the cognition enhancing properties of acute vs subchronic treatment with the selective 5-HT₆ receptor antagonist SB-271046 in unimpaired rats, as well as against scopolamine (cholinergic-) or MK-801 (glutamatergic-mediated) deficits.

Experimental approach:

The Morris water maze was used, measuring behaviour acquisition and retention, and swim speed. Other behavioural measures included yawning and motor activity. SB-271046 was given acutely before each trial or subchronically for 7 days before the trials. The AChE inhibitor galanthamine was also used alone or in combination with SB-271046.

Key results:

Subchronic treatment with SB-271046 improved acquisition in the Morris water maze, while the acute treatment only improved retention. Neither acute nor subchronic SB-271046 treatment reversed scopolamine-induced learning deficits. MK-801 induced learning impairment associated with a behavioural syndrome, reversed by acute, but not subchronic, SB-271046 treatment. Interestingly, combined treatment with galanthamine and SB-271046 reversed the scopolamine- or MK-801-induced learning impairments. Subchronic treatment with SB-271046 did not modify motor activity or the increased number of yawns, a cholinergic-mediated behaviour, induced by single administration of SB-271046.

Conclusions and implications:

These data suggest a potential therapeutic role of 5-HT₆ receptor antagonists such as SB-271046, alone or in combination with galanthamine, in the treatment of cognitive dysfunction, such as those seen in Alzheimer''s disease and schizophrenia.     

Attenuation of scopolamine induced deficits in navigational memory performance in rats by bis(7) tacrine, a novel dimeric AChE inhibitor

目的：研究他克林的双体衍生物双（７）他克林对东莨菪碱引起的大鼠记忆障碍的影响．方法：采用大鼠Ｍｏｒｉｓ水迷宫固定平台的程序研究空间记忆．以他克林为对照药．结果：东莨菪碱（０３ｍｇ·ｋｇ－１,ｉｐ）使大鼠到达平台的潜伏期明显长于生理盐水对照组．双（７）他克林（０３５μｍｏｌ·ｋｇ－１,ｉｇ或ｉｐ）和他克林（８５２μｍｏｌ·ｋｇ－１ｉｇ;４２６μｍｏｌ·ｋｇ－１ｉｐ）均可对抗东莨菪碱导致的空间记忆障碍;在灌胃及腹腔注射途径下,双（７）他克林的效价,分别强于他克林２４及１２倍．结论：双（７）他克林明显改善东莨菪碱导致的空间记忆障碍,其作用强于他克林．     

The effects of early postnatal stimulation on Morris water-maze acquisition in adult mice: genetic and maternal factors

 Following stressor exposure BALB/cByJ mice exhibit hypersecretion of corticosterone and marked brain catecholamine alterations. In addition, mice of this strain exhibit impairments of performance in a Morris water-maze, which may be exacerbated by footshock application. In the present investigation it was demonstrated that early-life handling of mouse pups (coupled with brief separation periods from the dam over the course of 21 days postpartum) reduced the learning impairments seen when mice were tested in the Morris water-maze at 120 days of age and also prevented stress-induced disturbances in this task. Likewise, cross-fostering BALB/cByJ mice with a C57BL/6ByJ dam prevented the performance deficits. In contrast, C57BL/6ByJ mice cross-fostered to a BALB/cByJ dam exhibited proficient performance. Thus, maternal factors may be important in determining the Morris water-maze disturbances, provided that this was applied on the BALB/cByJ genetic background. Stressor exposure exacerbated the performance disturbances in BALB/cByJ mice, while diazepam treatment disrupted Morris water-maze performance in both BALB/cByJ and C57BL/6ByJ mice. Paralleling the behavioral changes associated with handling, the stress-induced hypercorticosterone secretion characteristic of the BALB/cByJ mouse was attenuated by the early handling procedure. Stressor exposure also produced strain-dependent variations of NE and 5-HT, but these effects were not appreciably influenced by the handling procedure. These data are consistent with the proposition that performance disturbances of BALB/cByJ mice tested in the Morris water-maze task are associated with excessive hypothalamic-pituitary-adrenal reactivity. Moreover, it appears that the influence of early-life stimulation may interact with genetic factors in determining endocrine and behavioral stress responses. Received: 11 October 1995 / Final version: 22 June 1996     

Pro-oxidant activity of zuclopenthixol in vivo: differential effect of the drug on brain oxidative status of scopolamine-treated rats

Several clinical studies implicated oxidative stress in the pathophysiology of both psychosis and dementia. As dementia is commonly associated with psychosis, antipsychotic medications are of importance in the pharmacotherapy of dementia particularly as a number of antipsychotics were reported to demonstrate neuronal pro-oxidant and/or antioxidant properties. Impairment of learning and memory, as the most characteristic manifestation of dementia, could be induced in experimental animals by acute administration of scopolamine (SCO) with a resultant elevation in brain oxidative status. This study investigated the potential pro-oxidant and/or antioxidant activity of the antipsychotic drug zuclopenthixol acetate, as its effect on brain oxidative status has yet to be evaluated. A 2 x 3 between-subjects factorial design was used to investigate the simultaneous and interactive effects of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) and SCO on rat brain malondialdehyde, glutathione, glutathione peroxidase and superoxide dismutase levels/activities. Results revealed a significant pro-oxidant effect for both zuclopenthixol and SCO alone conditions. In addition, combined treatment of zuclopenthixol and SCO was found to be significantly different compared to either treatment conditions with regard to their effect on different brain oxidative stress indices. Such findings may have valuable implications in the pharmacotherapy of both psychosis and dementia.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).