Effect of oxiracetam on scopolamine-induced amnesia in the rat in a spatial learning task.

The effects of the nootropic agent 4-hydroxy-2-oxopyrrolidinoacetamide (oxiracetam) on memory and performance impairments induced by scopolamine were evaluated in the Morris water maze task. No effect was seen on the performance of rats when treated with oxiracetam (30 mg/kg, IP) alone. Task performance of scopolamine (0.2 mg/kg, SC)-treated rats was impaired as compared to that of control animals. The behavioral deficits expressed in the task by scopolamine treatment were attenuated by the same dose of oxiracetam.     

Protective effect of eurystatins A and B, new prolyl endopeptidase inhibitors, on scopolamine-induced amnesia in rats.

Eurystatins A and B, which are produced by Streptomyces eurythermus R353-21, potently inhibited Flavobacterium prolyl endopeptidase (PED) with IC50 values of 0.004 and 0.002 micrograms/ml, respectively, while no inhibition was observed against another 5 proteases, even at 100 micrograms/ml. The protective effect of eurystatins A and B against scopolamine (3 mg/kg, i.p.)-induced amnesia in rats was evaluated by the step-through one-trial passive avoidance method. When administered i.p. 30 min prior to the acquisition trial, both eurystatins A, at 2-8 mg/kg, and B, at 4-8 mg/kg, significantly protected rats from the amnesic effect of scopolamine without behavioral side effects.     

Oxiracetam prevents electroshock-induced decrease in brain acetylcholine and amnesia

In the rat, 1 min following electroshock (ECS) a 46 and 39% decrease in acetylcholine levels was found in the hippocampus and cerebral cortex, respectively. The decrease in the hippocampus was still statistically significant 30 min after ECS. The ECS applied 1 min after training also disrupted the performance of a passive avoidance conditioned response ('step down') tested 30 min later. Oxiracetam (100 and 300 mg/kg i.p.) administered 90 min before training prevented, in a dose-dependent manner, the decrease of acetylcholine in the cerebral cortex and hippocampus. Oxiracetam prevented the ECS disruption of the acquisition of a passive avoidance response. At the dose of 300 mg/kg the acetylcholine level 1 min after ECS was significantly higher than in the sham-treated rats. Piracetam at the same doses was inactive. These results support the hypothesis that oxiracetam may prevent the disruption of the conditioned response by acting on cortical and hippocampal cholinergic mechanisms.     

Effect of pyroglutamic acid stereoisomers on ECS and scopolamine-induced memory disruption and brain acetylcholine levels in the rat

The acquisition of a passive avoidance conditioned response was disrupted in the rat by electroconvulsive shock (ECS) and scopolamine administration. D,L-pyroglutamic acid (D,L-PCA) 500 and 1000 mg/kg, administered as arginine salt 120 min before the retest, prevented both the ECS and scopolamine-induced amnesia. Arginine alone was ineffective. Scopolamine brought about a 52 and 39% decrease, respectively, in cortical and hippocampal acetylcholine (ACh) levels, measured by means of a gas-chromatographic method. D,L-PCA 500 and 1000 mg/kg also prevented the decrease in brain ACh level. When the two isomers were studied separately, D-PCA was more effective than L-PCA and antagonized scopolamine-induced amnesia at the doses of 250 and 500 mg/kg. In conclusion, D,L-PCA is active on cortical and hippocampal cholinergic mechanisms and, like other 2-oxopyrrolidone derivatives, shows cognition-enhancing properties.     

Chronic treatment with an acetylcholine synthesis precursor,alpha-glycerylphosphorylcholine,alters brain parameters linked to cholinergic transmission and passive avoidance behavior

The present study extends previous observations on the acuta treatment with alpha-glycerylphosphorylcholine (GPC), a putative acetylcholine (ACh) precursor, and investigates the effect of chronic treatment with this drug on scopolamine-induced amnesia and on ACh release in the rat. The drug acutely administered antagonizes the amnesic effect of scopolamine (0.75 mg/kg s.c.) in passive avoidance experiments. The effect peaked at 600 mg/kg i.g. and lasted up to 30 hr. Potassium-stimulated release of ACh from slices of hippocampus and cerebral cortex was measured after various doses of GPC. The dose curve study indicated that GPC was able to increase ACh release in the hippocampus already at the dose of 75 mg/kg i.g. The maximum effect was obtained with 300 mg/kg i.g. (147% of the control values). The increase of the ACh release reached a maximum 3 hrfollowing the administration, then declined toward control values. In the cortex, the effect was much less pronounced and shorter than in the hippocampus. The repeated (100 and 300 mg/kg i.g.; 22 days) GPC administration effectively antagonized scopolamine-induced amnesia, indicating that there was no tolerance to this effect of GPC. While both doses were behaviorally active only 300 mg/kg was able to increase ACh release from hippocampus ( + 271 %) and cortex ( + 57%). The data support the hypothesis that GPC improves behavioral performance in passive avoidance through an action on cholinergic transmission. On the other hand, it should be stressed that the action on ACh release is observed in a narrow time window in contrast to the long lasting effect on behavior. It is tempting to speculate that the effect on ACh may be related to cortical activation and important but not sufficient to explain the antagonism of scopolamine-induced amnesia. Along this line other mechanisms, possibly triggered by the action on ACh, may contribute to mediate the behavioral effect of GPC. © 1992 Wiley-Liss, Inc.     

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).     

Calotropis procera: A potential cognition enhancer in scopolamine and electroconvulsive shock-induced amnesia in rats

Objectives:

Present study evaluates the effect of Calotropis procera (Apocynaceae) dry latex on cognitive function in rats using scopolamine and electroconvulsive shock (ECS) induced amnesia model.

Materials and Methods:

Male Wistar rats were pretreated with 200, 400 and 800 mg/kg of C. procera dry latex in scopolamine-induced amnesia model. Dose showing maximum effect in cognitive performance was selected and further evaluated using scopolamine and ECS-induced amnesia model for its effect on neurochemical enzymes and cognitive performance. Acetylcholinesterase (AChE) activity, β amyloid_1-42, and dopamine level were analyzed, while the cognitive performance was assessed by elevated plus maze, step-through passive avoidance test, and Morris water maze. Simultaneously, C. procera dry latex (25, 50, 100, 250, 500, and 1000 μg/mL) was screened for in vitro AChE inhibition assay.

Results:

Pretreatment with (200, 400 and 800 mg/kg) C. procera dry latex shows dose dependent increase in cognitive performance in scopolamine-induced amnesia. Further, pretreatment with the selected dose (800 mg/kg) showed significant improvement in transfer latency (P < 0.001, P < 0.01), escape latency (P < 0.05), time spent in target quadrant (P < 0.001) also significant decrease in AChE activity (P < 0.05), β amyloid_1-42 level (P < 0.001), and increase in dopamine level (P < 0.01) in rat brain homogenate when compared with scopolamine and ECS disease control groups. IC₅₀ for C. procera dry latex was found to be <1000 μg/mL.

Conclusions:

Pretreatment with C. procera dry latex (800 mg/kg) produced significant cognition enhancement by improving cognitive performance and decreasing the marker neurochemical enzyme activity in scopolamine and ECS-induced amnesia model.KEY WORDS: Acetylcholinesterase, Alzheimer''s disease, Dopamine, β amyloid1-42     

Effects of molsidomine on scopolamine-induced amnesia and hypermotility in the rat

Nitric oxide (NO) is hypothesized to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit nitric oxide synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The aim of this study was to assess in the rat the effects of the NO donor molsidomine (2 and 4 mg/kg, i.p.) on memory deficits caused by scopolamine. For this purpose, the object recognition task and the step-through passive avoidance procedure were chosen. In addition, the effects of molsidomine in antagonizing the scopolamine-induced hypermotility were also examined. Scopolamine at 0.2 mg/kg (object recognition) and 0.75 mg/kg (passive avoidance) disrupted acquisition in both the tasks and induced locomotor hyperactivity at the dose of 0.2 mg/kg. Molsidomine at either dose reversed the scopolamine-induced deficits in the object recognition paradigm but did not counteract the hypermotility and the deficits occurred in the passive avoidance test. These results suggest that to some extent, the NO donor molsidomine is involved in memory processing.     

The scopolamine-induced impairment of spatial cognition parallels the acetylcholine release in the ventral hippocampus in rats

We investigated the relationship between the induction of spatial cognition impairment in the 8-arm radial maze task and regional changes (ventral hippocampus (VH), dorsal hippocampus, frontal cortex, and basolateral amygdala nucleus) in brain acetylcholine (ACh) release using microdialysis in rats treated with muscarinic (M) receptor antagonists. In a behavioral study, two M1 antagonists, scopolamine (0.5 mg/kg, i.p. and 20 microg, i.c.v.) and pirenzepine (80 microg, i.c.v.), but not an M2 antagonist, AF-DX116 (40-80 microg, i.c.v.), disrupted spatial cognition in the 8-arm radial maze task. In brain microdialysis with Ringer's solution containing 0.1 mM eserine sulfate, scopolamine and AF-DX116, but not pirenzepine, increased ACh release in the VH. Moreover, in the bilateral injection of scopolamine (2 microg/side), the VH and dorsomedial thalamus nucleus were important regions for scopolamine-induced impairment of spatial cognition. A simultaneous determination of the behavioral changes revealed that scopolamine (0.5 mg/kg, i.p.) markedly decreased the ACh contents and also increased the ACh release in all regions tested. Especially, the changes in the ACh release of the VH closely paralleled the induction of the scopolamine-induced impairment of spatial cognition. These results suggest that the blocking balance between M1 and M2 muscarinic receptor in the VH therefore plays a major role in the spatial cognition impairment induced by scopolamine in the 8-arm radial maze task.     

Effects of nootropic drugs in a scopolamine-induced amnesia model in mice

Scopolamine (3 mg/kg IP) given before an acquisition trial, reduced the retention of a one-trial passive avoidance step through response in mice. A single administration of cholinergic agonists such as oxotremorine, BM-5, or arecoline, antagonized this amnesic effect of scopolamine. A significant anti-amnesic effect was also found with nootropic drugs such as piracetam and ucb L059, whereas ucb L060 (the enantiomer of ucb L059), oxiracetam and rolziracetam were shown to be ineffective. Moreover, ucb L059, administered twice daily for 3 days, counteracted the amnesic effects of scopolamine completely, whereas ucb L060 was again inactive. The results demonstrate that: (a) this model of impaired cognition by scopolamine is able to discriminate between closely related chemical substances and even stereoisomers; and (b) nootropic drugs, such as ucb L059, are more effective after repeated rather than after acute administration.     

Reversal effect of DM-9384 on scopolamine-induced acetylcholine depletion in certain regions of the mouse brain

The effect of a new cognition enhancer, DM-9384, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, on regional acetylcholine (ACh) levels and against scopolamine-induced ACh depletion was examined in mouse brain. In addition, the effects of DM-9384 were compared with those of oxiracetam, physostigmine and tacrine. Independent administration of DM-9384 (1, 3, 10 or 30 mg/kg, PO) or oxiracetam (10 or 50 mg/kg, PO) to mice had no effect on the ACh level in the hippocampus, frontal cortex, amygdala and striatum. Nevertheless, in all brain regions, pretreatment with DM-9384 significantly reduced the depletion of ACH induced by scopolamine (0.5 mg/kg, IP) in a non-dose-related bell-shaped manner. By contrast, oxiracetam attenuated the effect of scopolamine in the hippocampus, frontal cortex and striatum but not in the amygdala. Physostigmine (0.2 mg/kg, SC) significantly increased ACh levels and reversed the scopolamine-induced ACh depletion in all brain regions. Unlike physostigmine, tacrine (10 mg/kg, PO) increased ACh levels in the striatum but not in the other regions. Tacrine reversed the effect of scopolamine in the hippocampus, amygdala and striatum, but not in the frontal cortex. In the present study, DM-9384 more effectively inhibited scopolamine-induced depletion of ACh levels than the other agents tested. The results obtained indicate that the protective action of DM-9384 against scopolamine-induced amnesia is due to its ability to reverse the ACh depletion.     

Nasal administration of a cognition enhancer provides improved bioavailability but not enhanced brain delivery

Compound 1 [3,3-bis(4-pyridylmethyl)-1-phenylindolin-2-one] is an experimental cognition-enhancing drug now being developed for cognitive disorders. Oral bioavailability of 1 in rats was less than 10% of the dose. Nasal dosing improved bioavailability to greater than 50%. Brain levels of total radioactivity were measured after iv and nasal doses of radiolabeled 1. The ratio of AUCbrain:AUCplasma was the same by both routes, so nasal dosing did not enhance brain delivery. This is in contrast to other reports of large molecular weight substances and metals gaining direct access to the brain through the nasal epithelium.     

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia

Context:?Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged.

Objective:?To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice.

Materials and methods:?Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1?mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100?mg/kg, i.p.), and standard groups (piracetam 200?mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT_1/2 blocker (4?mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE.

Results and discussion:?FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE.

Conclusion:?FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.     

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。     

Psoralen and isopsoralen, two coumarins of Psoraleae Fructus, can alleviate scopolamine-induced amnesia in rats

In this study we have found that the crude extract of Psoraleae Fructus inhibited acetylcholinesterase activity in vitro and ameliorated impairment of the inhibitory avoidance response and of the water maze spatial performance caused by scopolamine in rats. Among all fractions, the chloroform fraction showed the best inhibitory effect on acetylcholinesterase activity and could reduce the scopolamine-induced inhibitory avoidance response impairment. Psoralen and isopsoralen, two major constituents of the chloroform fraction of Psoraleae Fructus identified by high performance liquid chromatography, also reduced the extent of the inhibitory avoidance response impairment. The results suggest that psoralen and isopsoralen are the major active ingredients of Psoraleae Fructus responsible for the progressive reversal of scopolamine-induced amnesia, whose effects are partially associated with inhibition of AchE activity and hence activation of the central cholinergic neuronal system.     

Meserine对胆碱酯酶活性及东莨菪碱诱导痴呆小鼠学习记忆的影响

目的：考察新型胆碱酯酶抑制剂Meserine对胆碱酯酶活性及东莨菪碱（Scopolamine）诱导的胆碱能障碍痴呆模型小鼠学习记忆的影响。方法：选取小鼠脑匀浆、血浆、人源重组AChE（rHuAChE）为体外酶源,测定Meserine抑制AChE／BuChE的活性、选择性及酶动力学。通过鼻腔给药后检测脑部AChE活性和ACh浓度评价Meserine对小鼠脑内胆碱能系统的调节。选用避暗及水迷宫实验考察Meserine对痴呆模型小鼠学习记忆功能的影响。结果：Meserine对AChE和BuChE都具有较好的抑制活性,IC50分别为（65．2±3．2）nmol／L和（86．7±4．9）nmol／L,并对rHuAChE呈现非竞争性抑制。经鼻给药Meserine可显著抑制脑内AChE活性、升高ACh水平,且二者变化的时程具有一致性,给药15min后,AChE抑制活性最强（26．9％）,ACh浓度最高（1269．0ng／g）。行为学实验结果显示,经鼻给药Meserine（10μg／kg）能显著改善东莨菪碱诱导的痴呆模型小鼠的工作记忆及空间学习能力,较模型组具有统计学差异（P〈0．OlVS东莨菪碱组）。结论：上述结果提示Meserine为强效非竞争性胆碱酯酶抑制剂,经鼻给药Meserine可通过调节脑内胆碱能系统有效改善东莨菪碱诱导的痴呆模型小鼠的学习记忆功能。     

Nanoparticle mediated brain targeted delivery of gallic acid: in vivo behavioral and biochemical studies for protection against scopolamine-induced amnesia

Abstract

Context: Gallic acid (GA) has well-documented antioxidant and CNS effects affecting glutathione, catalase and malonaldehyde levels in brain.

Objective: This study was designed to evaluate the anti-amnesic activity of pure GA in scopolamine (SC)-induced amnesic models and to enhance its effects using Tween 80®-coated nanoparticles.

Methods: GA-loaded chitosan nanoparticles (GANP) and corresponding Tween 80®-coated batch (cGANP) were formulated. Amnesia was induced by using SC (0.4?mg/kg, i.v.). GA, GANP, cGANP (dose equivalent to GA 10?mg/kg, i.p.) and positive control Piracetam (400?mg/kg, i.p.) were administered for successive 7 days to male Swiss albino mice. The in vivo pharmacodynamic study was performed using Morris water maze (MWM) and elevated plus maze (EPM) models; locomotor activity using photoactometer and brain acetyl cholinesterase (AChE) activity was also studied.

Key findings: GA-treated mice exhibited significant decrease in transfer latency in the EPM test; increase in time spent in target quadrant in MWM and reduced AChE activity. GA significantly reversed SC-induced amnesic activity. There was no significant change in locomotor activity of the mice by GA and its nanoparticle formulations. These effects were significantly increased by the administration of cGANP compared with pure GA administration but no significant change was observed for GANP.

Conclusion: GA possesses anti-amnesic activity by reversing the SC-induced amnesia which may be attributed to its anti-cholinesterase activity. Tween 80®-coated nanoparticle approach with improved brain targeting may serve as an effective approach to enhance its anti-amnesic effect.     

Coadministration of huperzine A and ligustrazine phosphate effectively reverses scopolamine-induced amnesia in rats

In the present study, whether coadministration of huperzine A (HA) and ligustrazine phosphate (LP) could effectively improve the memory deficits in association with ameliorating cholinergic impairment and oxidative stress in the scopolamine-induced amnesia rats was assessed. The effects of treatment with Coa [HA (0.14 mg/kg, i.g.) and LP (110 mg/kg, i.g.)] on amnesia were investigated in Morris water maze. Furthermore, the effects on the activities of acetylcholinesterase (AChE) and antioxidant enzymes within the cerebral cortex and hippocampus were evaluated, and the lipid peroxidation product malondialdehyde (MDA) was also analyzed. As a result, coadministration of HA and LP for 10 consecutive days could markedly reverse the scopolamine-induced learning and memory impairment determined by the Morris water maze test. Moreover, AChE activity was significantly inhibited, and superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities were significantly increased with a remarkable reduction in the level of MDA. In conclusion, coadministration of HA and LP effectively prevented cholinergic impairment and oxidative damage, thereby resulting in improvement of spatial learning memory in rats induced by scopolamine. The results suggested that coadministration of HA and LP might offer a novel poly-therapeutic drug regimen for preventing Alzheimer's disease (AD).     

Effect of L-DOPA on brain acetylcholine and choline in rats

The effect of acute and chronic administration of l-DOPA on brain acetylcholine and choline was investigated in male rats. A single injection of l-DOPA had no effect on the concentration of acetylcholine in the brains of normal, oxotremorine and physostigmine treated animals. Chronic treatment with l-DOPA produced a small but significant increase in brain acetylcholine concentrations; however, brain choline concentrations were unchanged. The increase in brain acetylcholine may be due to an inhibitory effect of dopamine on central cholinergic neurons.     

MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist-like properties.

1. The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5-(3-fluorophenyl)-2,4-dimethyl-3H-1,2,4-triazole-3-thione). 2. The 5-aryl-1,2,4-triazole, MDL 26,479, potently (0.22 +/- 0.05 mg kg-1) inhibited [3H]-flumazenil (Ro15-1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex. 3. Parenteral administration of MDL 26,479 (1 mg kg-1) or the benzodiazepine (BZD) inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg kg-1) increased cortical ex vivo binding of [3H]-hemicholinium-3 ([3H]-HC-3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg-1). 4. MDL 26,479 (20 microM) and DMCM (1 microM) increased excitation in the hippocampal long-term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil. 5. In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo. 6. Previous work showed that MDL 26,479 enhances learning acquisition in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)