PPARγ agonist pioglitazone improves scopolamine-induced memory impairment in mice

Objectives This study was conducted to evaluate the effects of exposure to pioglitazone, a peroxisome proliferator‐activated receptor agonist, on cognitive impairment induced by scopolamine, a muscarinic antagonist, in mice. Methods Pioglitazone (9 mg/kg, 18 mg/kg) was orally administered for 9 days at 30 min before intraperitoneal injection with scopolamine (0.8 mg/kg, i.p.). Cognitive function was evaluated by the passive avoidance test and the Morris water maze test on the 10th day after treatment. Changes in cholinergic system reactivity were also examined by measuring the acetylcholine, acetylcholinesterase and choline acetyltransferase in the hippocampus and cortex. Key findings Scopolamine injection induced impaired performance in the passive avoidance test and the water maze test and severe decrease of cholinergic system reactivity, as indicated by reduced acetylcholine levels, decreased choline acetyltransferase activity and increased acetylcholinesterase activity. Daily administration of pioglitazone significantly increased step‐through latency in passive avoidance test, and significantly decreased the escape latency, and increased the time spent in the platform quadrant in the Morris water maze test. Pioglitazone also protected against scopolamine‐induced cholinergic system deficit, including reduced acetylcholine levels, decreased choline acetyltransferase activity and increased acetylcholinesterase activity in the hippocampus or cortex. Conclusions Pioglitazone demonstrates a significant neuroprotective effect against scopolamine‐induced cholinergic system deficit and cognitive impairment.     

Cognitive-enhancing and antioxidant activities of iridoid glycosides from Scrophularia buergeriana in scopolamine-treated mice

The cognitive-enhancing activities of E-harpagoside and 8-O-E-p-methoxycinnamoylharpagide (MCA-Hg) isolated from Scrophularia buergeriana were evaluated in scopolamine-induced amnesic mice by the Morris water maze and by passive avoidance tests. E-harpagoside and MCA-Hg significantly improved the impairment of reference memory induced by scopolamine in the Morris water maze test. The mean escape latency, the mean path length and swimming movement were also improved by both compounds. In passive avoidance test, E-harpagoside and MCA-Hg (2 mg/kg body weight, p.o.) significantly ameliorated scopolamine-induced amnesia by as much as 70% of the level found in normal control mice. Donepezil, an acetylcholinesterase inhibitor and the most widely used drug for AD treatment was employed as a positive control. The activity of acetylcholinesterase was inhibited significantly by E-harpagoside or MCA-Hg within the cortex and hippocampus to a level similar to that observed in mice treated with donepezil (2 mg/kg body weight, p.o.). Moreover, treatment with E-harpagoside or MCA-Hg to scopolamine-induced amnesic mice significantly decreased TBARS level which was accompanied by an increase in the activities or contents of glutathione reductase, SOD and reduced GSH. We believe these data demonstrate that E-harpagoside or MCA-Hg exerted potent cognitive-enhancing activity through both anti-acetylcholinesterase and antioxidant mechanisms.     

Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice

Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), which is widely used in treatment of type 2 diabetes, has shown some therapeutic effect in Alzheimer's disease. In this study, effects of acute pioglitazone on acquisition, consolidation and retrieval of memory, and also the involvement of nitric oxide (NO) in the effects of pioglitazone on spatial recognition memory has been investigated in a two-trial recognition Y-maze test and passive avoidance in mice. Memory impairment was induced by scopolamine (1 mg/kg, i.p.). Pioglitazone (10 and 20 mg/kg, p.o.) was administrated prior to either acquisition, consolidation or retention trials, while L-NAME (N-nitro-l-arginine methyl ester), a non-specific NO synthase inhibitor, was administered (10 mg/kg, i.p.) 30 min before each trial. Results: 1) pioglitazone improved the acquisition of recognition spatial memory-impaired by scopolamine; L-NAME dramatically reversed improving effects of pioglitazone on memory acquisition; 2) pioglitazone did not change the consolidation of spatial memory, impaired by scopolamine; 3) pioglitazone improved the retrieval of spatial memory and L-NAME did not alter the beneficial effect of pioglitazone; 4) pioglitazone did not affect scopolamine-induced cognitive impairments in the passive avoidance test.The present study demonstrates the beneficial effect of acute pioglitazone administration on acquisition and retrieval of scopolamine-induced cognitive deficits. This effect was reversed only in acquisition phase by nitric oxide synthase inhibitor, L-NAME, therefore, it could be concluded that NO might be involved in the pioglitazone beneficial effect of spatial memory acquisition.     

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。     

Protective effect of N-acetylcysteine on bisphenol A-induced cognitive dysfunction and oxidative stress in rats

Bisphenol A (BPA) is commonly used as a monomer in polycarbonate plastics. The present study was designed to investigate the effect of BPA on cognitive functions and oxidative stress in the brain tissue of rats and if co-administration of N-acetylcysteine (NAC), an antioxidant, can modulate the effect of BPA on cognitive functions and prevent any possible oxidative stress. The BPA was administered per orally (p.o) in two doses 2 and 20 μg/kg for 28 days. Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and spatial navigation task on Morris water maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and reduced glutathione (GSH) levels. A significant reduction in SDL, and prolongation of latency in spatial navigation task were observed in BPA (2 and 20 μg/kg) treated group as compared to control group. The co-administration of NAC (100 mg/kg, p.o) antagonized the effect of BPA on SDL and spatial navigation test. NAC treatment also attenuated the BPA-induced increased MDA levels and decreased GSH levels in brain. Results of the present study show that NAC has potential to reverse cognitive dysfunction and oxidative stress induced by BPA exposure in rats.     

Acteoside of Callicarpa dichotoma attenuates scopolamine-induced memory impairments

We previously reported that ten phenylethanoid glycosides including acteoside isolated from the leaves and twigs of Callicarpa dichotoma significantly attenuated glutamate-induced neurotoxicity. In the present study, we examined anti-amnesic activity of acteoside using scopolamine-induced (1 mg/kg body weight, s.c.) amnesic mice with both passive avoidance and Morris water maze tests. Acute oral treatment (single administration prior to scopolamine treatment) of mice with acteoside (1.0, 2.5 mg/kg body weight) significantly mitigated scopolamine-induced memory deficits in the passive avoidance test. It is interesting to note that prolonged oral daily treatment of mice with much lower amount (0.1 mg/kg body weight) of acteoside for 10 d reversed the scopolamine-induced memory deficits. In the Morris water maze, prolonged oral treatment with acteoside (prolonged daily administration of 1.0 mg/kg body weight for 10 d) significantly ameliorated scopolamine-induced memory deficits showing the formation of long-term and/or short-term spatial memory. We suggest, therefore, that acteoside has anti-amnesic activity that may ultimately hold significant therapeutic value in alleviating certain memory impairment observed in Alzheimer's disease.     

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.     

Pioglitazone improves visceral sensation and colonic permeability in a rat model of irritable bowel syndrome

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.     

吡格列酮对脂多糖引起的大鼠学习记忆障碍及海马炎症反应的影响

目的研究吡格列酮(pioglitazone,Pio)能否对抗脂多糖(lipopolysaccharide,LPS)所致的大鼠学习记忆障碍及海马炎症反应。方法取SD大鼠40只,随机分为4组:生理盐水对照组,LPS损伤组,LPS+Pio 40和80 mg.kg-1组。灌胃给予Pio 2 d后,脑室注射LPS 5μl(1.0 mmol·L-1),生理盐水对照组注射等量生理盐水。脑室注射后d 2进行Morris定位航行实验,连续5 d,在d 6进行空间探索实验,训练期间继续给药。d 7,快速取海马CA1区,Western blot方法观察白介素-1β(Interleukin-1β,IL-1β),诱导型一氧化氮合酶(Inducible Nitric Oxide Synthase,iNOS),半胱氨酸天冬氨酸蛋白酶(caspase)3,caspase-9及多聚ADP-核糖聚合酶(PARP)蛋白表达水平的变化。RT-PCR检测IL-1β和iNOS的mRNA表达水平。结果脑室内注射LPS,大鼠出现明显的空间学习记忆障碍,表现为逃避潜伏期较生理盐水对照组明显延长(P<0.05),在原平台象限游泳时间占总游泳时间的百分比明显降低(P<0.01)。Western蛋白印迹及RT-PCR结果显示注射LPS后,与对照组相比海马CA1区IL-1β、iNOS蛋白及mRNA表达水平明显增加(P<0.01),活化的caspase-3,caspase-9蛋白表达水平明显增高,分子质量116 ku PARP表达明显减少,而分子质量89 ku劈切PARP表达明显增加(P<0.01)。Pio(40和80 mg.kg-1)能改善大鼠学习记忆功能,对抗LPS引起的海马CA1区IL-1β、iN-OS、活化的caspase-3、活化的caspase-9表达增加,也可明显抑制LPS所致的PARP表达的改变(P<0.01)。结论吡格列酮能够改善大鼠学习记忆功能,抑制LPS引起的海马炎症反应。     

Effect of wild ginseng on scopolamine‐induced acetylcholine depletion in the rat hippocampus

Objectives The ameliorating effects of wild ginseng on learning and memory deficits were investigated in rats. Methods Rats were treated daily with wild ginseng or cultivated ginseng for 7 days at 30 min before scopolamine injection (2 mg/kg, i.p.). After inducing cognitive impairment by the administration of scopolamine, behavioural assessment using the Morris water maze was performed. Changes in cholinergic system reactivity were also examined by measuring the immunoreactive neurons of choline acetyltransferase and the reactivity of acetylcholinesterase in the hippocampus. Key findings Scopolamine injection induced impaired performance in the water maze test and severe cell losses in hippocampal cholinergic neurons, as indicated by decreased choline acetyltransferase immunoreactivity and increased acetylcholinesterase reactivity. Daily administration of wild ginseng produced a significant improvement in the escape latency for finding the platform in the Morris water maze and reduced the loss of cholinergic immunoreactivity in the hippocampus. The reduced expression of brain‐derived neurotrophic factor mRNA due to the scopolamine injection was recovered to normal levels by the administration of wild ginseng. Conclusions Wild ginseng demonstrates a significant neuroprotective effect against scopolamine‐induced neuronal and cognitive impairment.     

TAK—147逆转东莨菪碱诱发的大鼠空间记忆障碍

目的:研究和阐明TAK-147对东莨菪碱诱发的大鼠空间记忆损伤的作用.方法:采用Morris水迷宫的程序研究大鼠的空间记忆,利用开场实验方法测定动物自发活动量.结果:在水迷宫的学习过程中,腹腔内注射东莨菪碱(0.4mg/kg,ip)明显延长大鼠上台的潜伏期,而腹腔内注射TAK-147或donepezil(多奈哌齐)能剂量依赖性地改善东莨菪碱诱发的记忆损伤,两药在0.1-1.0mg/kg的剂量时具有显著性差异.在记忆的再生过程中,腹腔内注射东莨菪碱(1.5mg/kg,ip)引起空间记忆再生过程的障碍分别被TAK-147(0.1,0.3和1.0mg/kg)、多奈哌齐(0.3和1.0mg/kg)以及他克林(3和5mg/kg)显著性改善.TAK-147的作用比多奈哌齐略强却明显强于他克林.此外,在开场实验中,TAK-147和多奈哌齐与生理盐水和东莨菪碱相比,对大鼠运动量未产生明显改变.结论:TAK-147在空间认知功能上起重要的作用,进一步证明TAK-147能够成为一个治疗阿尔采默病的理想的胆碱酯酶抑制药.     

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).     

新型胆碱酯酶抑制剂双（7）—他克林减弱东莨菪碱引起的大鼠空间记 …

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Ｍｏｒｒｉｓ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）和他克林（８     

The ameliorating effect of the extract of the flower of Prunella vulgaris var.lilacina on drug-induced memory impairments in mice

Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and its flowers are used to treat inflammation in traditional Chinese medicine. In the present study, we studied the effects of the ethanolic extract of the flower of P. vulgaris var. lilacina (EEPV) on drug-induced learning and memory impairment using the passive avoidance, the Y-maze, and the Morris water maze tasks in mice. EEPV (25 or 50 mg/kg, p.o.) significantly ameliorated scopolamine-induced cognitive impairments in the passive avoidance and Y-maze tasks (P < 0.05). In the Morris water maze task, EEPV (25 mg/kg, p.o.) significantly shortened escape latencies in training-trials. Furthermore, swimming times within the target zone during the probe-trial were significantly increased as compared with scopolamine-treated mice (P < 0.05). In addition, the reduced latency induced by MK-801 treatment in the passive avoidance task was ameliorated by EEPV (25 mg/kg, p.o.) (P < 0.05). Additionally, the ameliorating effect of EEPV on scopolamine-induced memory dysfunction was antagonized by a sub-effective dose of MK-801. These results suggest that EEPV would be useful for treating cognitive impairments induced by cholinergic dysfunction, and that it exerts its effects via NMDA receptor signaling.     

羟基查尔酮类衍生物C8对东莨菪碱致痴呆小鼠学习记忆的影响

目的：观察羟基查尔酮类衍生物C8对东莨菪碱诱导的记忆障碍小鼠学习记忆的影响。方法：实验小鼠除空白对照组、东莨菪碱组（模型组）灌服0.5%CMC-Na溶液外,C8给药组（高、低2个剂量组）灌服C8,阳性对照组灌服吡拉西坦,连续灌胃22d。从第15天起进行Morris水迷宫试验,连续8d。结果：C8能明显缩短定位航行实验中模型小鼠的逃避潜伏期,明显延长空间探索实验中模型小鼠在原平台所在象限的游泳时间。结论：C8对东莨菪碱引起的小鼠学习记忆能力障碍有改善作用。     

Beneficial effects of resveratrol on scopolamine but not mecamylamine induced memory impairment in the passive avoidance and Morris water maze tests in rats

Resveratrol (3,5,4-trihydroxy-trans-stilbene), which is found in grapes and red wine has been shown to protect neuronal cells with its antioxidant activity, improve memory function in dementia and reverse acetylcholine esterase (AChE) activity. The aim of this study was to investigate the effect of resveratrol on emotional and spatial memory in naive rats, as well as on scopolamine- and mecamylamine-induced memory impairment in the passive avoidance and Morris water maze (MWM) tests. Resveratrol (12.5, 25 and 50 mg/kg), scopolamine (0.6 mg/kg) and mecamylamine (10 mg/kg) were administered to male Wistar rats. In the passive avoidance test, there was no significant difference in the first day latency between all groups, whereas scopolamine and mecamylamine significantly shortened the second day latency compared to the control group. Resveratrol reversed the effect of scopolamine at all doses used, but it had no effect on mecamylamine-induced memory impairment in the passive avoidance test. Both scopolamine and mecamylamine significantly decreased the time spent in the escape platform quadrant during the probe trial of the MWM test compared to the control group. Resveratrol reversed the effect of scopolamine at all doses, but did not change the effect of mecamylamine in the MWM test. There were no significant differences in the locomotor activities of any of the groups. In conclusion, we suggested that resveratrol had improving effects on learning and memory by acting on muscarinic cholinergic receptors and at least in part, may reverse AChE activity.     

Beneficial effects of Urtica dioica on scopolamine-induced memory impairment in rats: protection against acetylcholinesterase activity and neuronal oxidative damage

This study was conducted to investigate protective effects of Urtica dioica extract on acetylcholinesterase (AChE) activity and the oxidative damage of brain tissues in scopolamine-induced memory impairment model. The rats were treated with (1) saline (control), (2) scopolamine, and (3–5) the plant extract (20, 50, or 100?mg/kg) before scopolamine. The traveled distance and the latency to find the platform in Morris water maze (MWM) by scopolamine-treated group were longer while the time spent in target quadrant was shorter than those of the control. Scopolamine decreased the latency to enter the dark in passive avoidance test. Besides, it also increased AChE activity and malondialdehyde (MDA) concentration in the hippocampal and cortical tissues while decreased thiols content and superoxide dismutase (SOD) and catalase (CAT) activities in the brain (p?<?0.01–p?<0.001). Treatment by the extract reversed all the effects of scopolamine (p?<?0.05–p?<0.001). According to the results of present study, the beneficial effects of U. dioica on memory can be attributed to its protective effects on oxidative damage of brain tissue and AChE activity.     

Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines

Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated.Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells.     

Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation

Stigmasterol, a kind of phytosterol, is present in small amounts in various foods. In the present study, we investigated the effects of stigmasterol on scopolamine-induced memory impairments using the passive avoidance and the Morris water maze tasks in mice. In addition, changes in memory-related molecules, including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were examined following the administration of stigmasterol. Scopolamine-induced memory impairments were significantly attenuated by the administration of stigmasterol (10mg/kg) in the passive avoidance task. In the Morris water maze task, the escape latencies were significantly decreased in the stigmasterol-treated group compared to the scopolamine-treated group during the training phase. The swimming times within the target zone during the probe trial were significantly increased as compared to scopolamine-treated mice. Furthermore, the ameliorating effect of stigmasterol on scopolamine-induced memory dysfunction was blocked by a sub-effective dose of dizocilpine (MK-801), an NMDA receptor antagonist, and tamoxifen, an estrogen receptor antagonist, in the passive avoidance task. In addition, the expression levels of phosphorylated ERK and CREB in the hippocampus were significantly increased by stigmasterol, which was blocked by tamoxifen or MK-801 with scopolamine. These results suggest that stigmasterol-induced cognitive ameliorative effects are mediated by the enhancement of cholinergic neurotransmission system via the activation of estrogen or NMDA receptors.