Animal Models Of Amnesia Research Articles

Neuroprotective Impact Of Zingerone And Gramine On Scopolamine-Induced Amnesia Model

Progressive memory loss is a symptom of many dangerous neurological diseases, such as Alzheimer's disease and forgetfulness. The goal of this study was to see how well bioactive molecules worked in animal models of amnesia caused by scopolamine. Ginger has a lot of Zingerone (Zn), which makes up about 9.25% of the total amount. Gramine (Ga) is a nonterpenoid indole alkaloid that is found in plants like barley and wheat. It is also known as donaxine. Acute toxicity tests were done on both of the drugs. As an animal model for study scopolamine induced amnesia in rat were selected and as behavioural evaluation the Morris water maze (MWM) and elevated plus maze were used to measure behavioural changes (EPM). In case of biochemical evaluation were the glutathione (GSH), lipid peroxidation (LPO), catalase (CAT), and AchE in the serum levels were performed. Histopathological imaging also performed. The animals were administered as per following grouping Zn (75,125,250 mg/kg p.o.) and Ga (13, 27.5,55 mg/kg), standard administered donepezil (1 mg/kg p. o.) In This Zn, Ga and Donepezil reading demonstrate significant improvement in antioxidant defence and reversed the biochemical (LPO, GSH), enzymatic (AchE) and behavioural changes which was observed by MWM and EPM as compared to Positive control so as per above observation Zn and Ga significantly fixed the memory problems caused by scopolamine so based on the above discussion, both drugs may be able to fight Alzheimer's.

Neuroprotective Activity of Polyphenol-Rich Ribes diacanthum Pall against Oxidative Stress in Glutamate-Stimulated HT-22 Cells and a Scopolamine-Induced Amnesia Animal Model

Ribes diacanthum Pall, a native Mongolian medicinal plant, has been reported to show antioxidant activities due to its polyphenol and flavonoid content, and is especially rich in the ethyl acetate fraction from an 80% methanol extraction (RDP). We assessed the cytoprotective effect of RDP on glutamate-caused oxidative stress and apoptosis in mouse hippocampal neuronal cells (HT-22 cells). Cell viability was significantly recovered by RDP treatment. Also, RDP effectively decreased the glutamate-induced production of intracellular reactive oxygen species (ROS). In flow cytometric analysis, apoptotic cells and the mitochondrial membrane potential were suppressed by RDP. In the Western blotting analysis, we found that RDP not only decreased the release of apoptotic proteins but also recovered anti-apoptotic protein. Additionally, RDP enhanced the antioxidant defense system by regulating the expression of antioxidant enzymes. Furthermore, treatment with RDP activated the BDNF/TrkB pathway. In accordance with the in vitro results, RDP meliorated memory deficit by defending hippocampal neuronal cells against oxidative damage in scopolamine-injected mice. Taken together, our present study showed that RDP exerted antioxidant and neuroprotective actions against oxidative stress. Therefore, RDP might facilitate the development of candidates for functional health foods for neurodegenerative disorders.

Evaluation of antiamnesic activity of Salvia multicaulis essential oil on scopolamine-induced amnesia in rats: in vivo and in silico approaches

Plants of genus Salvia have been used in folk medicine for wound healing, in the alleviation of stomach, liver, and rheumatism pains, as antioxidant, cognitive-enhancer, sedative and antiseptic, stimulant and tonic agents. The present study aimed to evaluate whether Salvia multicaulis essential oil (1% and 3%) administered for 21 days attenuates cognitive deficits and exhibits anxiolytic and antidepressant-profile in the scopolamine-induced amnesia in rats. Rats were randomly divided into six groups (n = 6): (1) control, (2) scopolamine (Sco, 0.7 mg/kg) (3, 4) S. multicaulis essential oil treatment groups (SEO, 1% and 3%), (5) diazepam (DIAZ, 1.5 mg/kg) and (6) tramadol (TRM, 10 mg/kg). To establish an animal model of amnesia, Sco (0.7 mg/kg), a muscarinic acetylcholine receptor antagonist, was injected into male Wistar rats. Y-maze (memory), radial arm-maze (memory), elevated plus-maze (anxiety), and forced swimming (depression) tests were employed. Molecular interactions of chemical compounds from the essential oil with the GABAA receptor was explored via molecular docking experiments. Using behavioral tests, we demonstrated that inhalation of S. multicaulis essential oil exerts significant antiamnesic activity as well as anxiolytic-antidepressant-like effects in the Sco-treated rats.Our data revealed that S. multicaulis oil could act as a promising phytopharmaceutical agent for improving dementia-related abnormalities.

Differential Outcomes Training Ameliorates Visual Memory Impairments in Patients With Alzheimer's Disease: A Pilot Study.

It is well known that Alzheimer’s disease (AD), the most common form of dementia, is associated with deficits in cognitive processes including visual memory impairments. One technique that might be used to ameliorate these impairments is the differential outcomes procedure (DOP) that involves associating each to-be-remembered stimulus with a specific outcome.Objective: Previous research has demonstrated that the DOP can be used to reduce or eliminate the learning and memory deficits associated with animal models of amnesia and dementia. Furthermore, this procedure has been shown to improve delayed facial recognition in healthy older adults as well as in patients diagnosed with AD. The main aim of the present study is twofold: to extend these findings to other types of visual stimulus and to investigate the effect of the DOP in memory retention in AD patients.Method: Ten patients diagnosed with AD and 10 healthy controls participated in this study. The experiment included two phases. In the first one, they had to perform a delayed matching-to-sample task. In the second phase, participants performed a recognition memory task, designed to assess long-term retention, 1 h and 1 week after the training.Results: Participants showed a better memory-based performance as well as a higher long-term retention of the information when trained under the differential outcomes condition, relative to the non-differential outcomes condition.Conclusions: The DOP seems to be an effective, easy-to-implement, technique to enhance visual memory in AD patients.

Design and development of novel p-aminobenzoic acid derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer’s disease

Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE.

The passive avoidance memory improving effect of curcumin in young adult mice: Considering hippocampal MMP-2, MMP-9 and Akt/GSK3β

Curcumin has been suggested as a candidate for the prevention of Alzheimer’s disease. Recently, a human study has revealed that curcumin enhances cognition in non-demented aged population. Although the neuroprotective effect of curcumin has been shown in some animal models of amnesia, no study has showed its memory improving effect in intact adult animals. This study aimed to assess the effect of curcumin on passive avoidance memory in adult young mice. Additionally, the hippocampal contents of MMP-2, MMP-9 and Akt/GSK3β were determined. Male mice weighing 20–25 g were trained in passive avoidance apparatus. Curcumin 50 or 100 mg/kg/po (according to our initial tests) or its vehicle was administered for 10 days. On day 10 the training was done and the retention trial was performed 24 h later. At the complement of behavioral studies, the hippocampal tissue was isolated and western blot analysis was performed for MMP-2, MMP-9 and Akt/GSK3β. The results indicated that curcumin improved passive avoidance memory. Moreover, it elevated hippocampal MMP-2,9 and p-Akt/t-Akt while it decreased the activated form of GSK-3β. According to these findings, it seems that curcumin improves memory and affects hippocampal MMP-2, MMP-9 and Akt/GSK3β signaling molecules in young adult animals.

Development of Piperazinediones as dual inhibitor for treatment of Alzheimer's disease

Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50 = 32.45 ± 0.044, 28.65 ± 0.029, BuChE, IC50 = 157.95 ± 0.264, 160.58 ± 0.082 and MMP-2, IC50 = 36.83 ± 0.015, 19.57 ± 0.005 (nM). In the enzyme kinetics study, lead molecule 46 showed non-competitive inhibition of AChE with Ki = 7 nM and competitive inhibition of MMP-2 with Ki = 20 nM. Compounds 52 and 46 inhibited AChE-induced Aβ aggregation at 20 μM. The compounds also exhibited in-vitro antioxidant potential in DPPH assay. Further, compound 46 was found to be a promising neuroprotective agent in MC65 cells. Lead molecule 46 significantly enhanced working memory in scopolamine induced amnesia animal model at dose of 5 mg/kg dose. The mitochondrial membrane potential was restored in animals when treated with compounds 52 and 46.

Neuroprotective Effect and Molecular Mechanism of [6]-Gingerol against Scopolamine-Induced Amnesia in C57BL/6 Mice.

We have investigated the neuroprotective and memory enhancing effect of [6]-gingerol (GIN), a pungent ingredient of ginger, using an animal model of amnesia. To determine the neuroprotective effect of GIN on cognitive dysfunction, scopolamine (SCO, 1 mg/kg, i.p.) was injected into C57BL/6 mice, and a series of behavioral tests were conducted. SCO-induced behavior changes and memory impairments, such as decreased alteration (%) in Y-maze test, increased mean escape latency in water maze test, diminished step-through latency in passive avoidance test, and shortened freezing time in fear condition test, were significantly prevented and restored by the oral administration of GIN (10 or 25 mg/kg/day). To further verify the neuroprotective mechanism of GIN, we have focused on the brain-derived neurotrophic factor (BDNF). The administration of GIN elevated the protein expression of BDNF, which was mediated via the activation of protein kinase B/Akt- and cAMP-response element binding protein (CREB) signaling pathway. These results suggest that GIN may have preventive and/or therapeutic potentials in the management of memory deficit and cognitive impairment in mice with amnesia.

Scopolamine-induced passive avoidance memory retrieval deficit is accompanied with hippocampal MMP2, MMP-9 and MAPKs alteration

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive deficit. The observed amnesia in the early stages of AD is suggested to be a retrieval problem, rather than encoding and consolidation deficit. According to the cholinergic hypothesis of AD, scopolamine is used to induce an animal model of amnesia. Howbeit the effect of scopolamine on memory retrieval is contradictory. This study aimed to assess the effect of scopolamine on passive avoidance memory retrieval. Additionally according to the reported changes of MMP-2, MMP-9 and MAPKs (ERK, P38 and JNK) in AD pathology the hippocampal contents of these proteins were determined. Male NMRI mice weighing 20–25g were trained in passive avoidance apparatus. The drug or its vehicle was injected 24h after training (30min before retention test). The hippocampal tissue was isolated and western blot analysis was done for MMP-2, MMP-9 and MAPKs (ERK, P38 and JNK). The results indicated that scopolamine (1mg/kg) disrupts passive avoidance memory retrieval. This scopolamine treatment resulted in hippocampal MMP-2 and MMP-9 decline while increased MAPKs in the hippocampus. These results suggest that cholinergic system has an important role in learnt memory retrieval. It might also suggest the positive role of MMP-2 and MMP-9 in this phase of memory while propose that MAPKs affect negatively the reactivation of memory which is compatible with MAPKs activation in AD.

Repeated administration of almonds increases brain acetylcholine levels and enhances memory function in healthy rats while attenuates memory deficits in animal model of amnesia.

Dietary nutrients may play a vital role in protecting the brain from age-related memory dysfunction and neurodegenerative diseases. Tree nuts including almonds have shown potential to combat age-associated brain dysfunction. These nuts are an important source of essential nutrients, such as tocopherol, folate, mono- and poly-unsaturated fatty acids, and polyphenols. These components have shown promise as possible dietary supplements to prevent or delay the onset of age-associated cognitive dysfunction. This study investigated possible protective potential of almond against scopolamine induced amnesia in rats. The present study also investigated a role of acetylcholine in almond induced memory enhancement. Rats in test group were orally administrated with almond suspension (400 mg/kg/day) for four weeks. Both control and almond-treated rats were then divided into saline and scopolamine injected groups. Rats in the scopolamine group were injected with scopolamine (0.5 mg/kg) five minutes before the start of each memory test. Memory was assessed by elevated plus maze (EPM), Morris water maze (MWM) and novel object recognition (NOR) task. Cholinergic function was determined in terms of hippocampal and frontal cortical acetylcholine content and acetylcholinesterase activity. Results of the present study suggest that almond administration for 28 days significantly improved memory retention. This memory enhancing effect of almond was also observed in scopolamine induced amnesia model. Present study also suggests a role of acetylcholine in the attenuation of scopolamine induced amnesia by almond.

Protective effects of aloe-emodin on scopolamine-induced memory impairment in mice and H2O2-induced cytotoxicity in PC12 cells

Aloe-emodin (AE) is one of the most important active components of Rheum officinale Baill. The present study aimed to investigate that AE could attenuate scopolamine-induced cognitive deficits via inhibiting acetylcholinesterase (AChE) activity and modulating oxidative stress. Kunming (KM) mice were received intraperitoneal injection of scopolamine (2mg/kg) to induce cognitive impairment. Learning and memory performance were assessed in the Morris water maze (MWM). After behavioral testing, the mice were sacrificed and their hippocampi were removed for biochemical assays (superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA), AChE and acetylcholine (ACh)). In vitro, we also performed the AChE activity assay and H2O2-induced PC12 cells toxicity assay. After 2h exposure to 200μM H2O2 in PC12 cells, the cytotoxicity were evaluated by cell viability (MTT), nitric oxide (NO)/lactate dehydrogenase (LDH) release and intracellular reactive oxygen species (ROS) production. Our results confirmed that AE showed significant improvement in cognitive deficit in scopolamine-induced amnesia animal model. Besides, it increased SOD, GPx activities and ACh content, while decreased the level of MDA and AChE activity in AE treated mice. In addition, AE was found to inhibit AChE activity (IC50=18.37μg/ml) in a dose-dependent manner. Furthermore, preincubation of PC12 cells with AE could prevent cytotoxicity induced by H2O2 and reduce significantly extracellular release of NO, LDH and intracellular accumulation of ROS. The study indicated that AE could have neuroprotective effects against Alzheimer’s disease (AD) via inhibiting the activity of AChE and modulating oxidative stress.

Intact Memory for Irrelevant Information Impairs Perception in Amnesia

SummaryMemory and perception have long been considered separate cognitive processes, and amnesia resulting from medial temporal lobe (MTL) damage is thought to reflect damage to a dedicated memory system. Recent work has questioned these views, suggesting that amnesia can result from impoverished perceptual representations in the MTL, causing an increased susceptibility to interference. Using a perceptual matching task for which fMRI implicated a specific MTL structure, the perirhinal cortex, we show that amnesics with MTL damage including the perirhinal cortex, but not those with damage limited to the hippocampus, were vulnerable to object-based perceptual interference. Importantly, when we controlled such interference, their performance recovered to normal levels. These findings challenge prevailing conceptions of amnesia, suggesting that effects of damage to specific MTL regions are better understood not in terms of damage to a dedicated declarative memory system, but in terms of impoverished representations of the stimuli those regions maintain.

Effects of a new synthetic butyrylcholinesterase inhibitor, HBU-39, on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus in a scopolamine-induced amnesia animal model

In this study, we synthesized [1-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-5-(1,2-dithiolan-3-yl)pentan-1-one, HBU-39], a (α)-lipoic acid derivative, and found this compound strongly inhibited butyrylcholinesterase (BuChE) in an in vitro experiment. We also examined the effects of HBU-39 on cell proliferation and neuroblast differentiation using the specific markers Ki67 and doublecortin (DCX), respectively, in the hippocampal dentate gyrus of a rat model of scopolamine-induced amnesia. For this, scopolamine was subcutaneously administered for 28days by an ALzet osmotic minipump (44mg/mL delivered at 2.5μL/h). HBU-39 (1mg/kg per day) and galantamine (an acetylcholinesterase inhibitor used as a control; 5mg/kg per day) were intraperitoneally administered for 28days. The administration of scopolamine significantly decreased the mean number of Ki67- and DCX-immunoreactive cells in the dentate gyrus. However, treatment with both HBU-39 and galantamine significantly ameliorated the reductions in cell proliferation and neuroblast differentiation. In particular, the mean number of Ki67- and DCX-immunoreactive cells was prominently abundant in the HBU-treated group compared to that in the galantamine-treated group. These results suggest that the BuChE inhibitor, HBU-39, can ameliorate the scopolamine-induced reductions of cell proliferation and neuroblast differentiation, and HBU-39 may be applicable to amnesia patients to promote memory functions.

Effects of Nelumbo nucifera Rhizome Extract on Cell Proliferation and Neuroblast Differentiation in the Hippocampal Dentate Gyrus in a Scopolamine‐induced Amnesia Animal Model

A large aquatic herb, Nelumbo nucifera Gaertn, has psychopharmacological effects similar to minor tranquillizers and antistress agents. This study examined the effects of Nelumbo nucifera rhizome extracts (NRE) on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG) of a rat model of scopolamine-induced amnesia. Immunohistochemical markers included Ki67, an endogenous marker for active cell cycle, and doublecortin (DCX), a marker for immature neurons and migratory neuroblasts. Scopolamine was administered for 28 days via an ALzet minipump (44 mg/mL delivered at 2.5 µL/h). NRE was administered by gavage, 1 g/kg per day for 28 days. The administration of scopolamine significantly reduced the number of Ki67- and DCX-immunoreactive cells in the DG, whereas scopolamine did not induce any significant changes in mature neurons in the DG. The administration of NRE significantly ameliorated the scopolamine-induced reduction of Ki67- and DCX-immunoreactive cells in the DG. In addition, the administration of NRE significantly restored the scopolamine-induced reduction of brain-derived neurotrophic factor in DG homogenates. These results suggest that NRE can ameliorate the scopolamine-induced reductions of cell proliferation, neuroblast differentiation and BDNF levels.

Heightened susceptibility to interference in an animal model of amnesia: Impairment in encoding, storage, retrieval – or all three?

There has recently been a resurgence in the idea that amnesia may be characterized by an increased susceptibility to interference. In the present study we tested this idea using a well-controlled and well-established animal model of amnesia: impairment in object recognition following perirhinal and postrhinal cortical (PPRh) damage. We used this paradigm to test whether memory impairment was exacerbated by the interpolation of a potentially interfering item either before (proactive interference) or after (retroactive interference) the to-be-remembered item. Rats with PPRh damage were impaired in object recognition memory, with a minimal delay, when the interfering stimulus was perceptually similar to the test stimuli. When the interfering stimulus was less perceptually similar to the test stimuli, the PPRh-lesioned rats performed similarly to Controls. Both proactive and retroactive interference were observed, and both depended on the similarity of the interfering item to the test items. These findings provide support for the idea that amnesia can indeed be characterized by increased vulnerability to interference, and we illustrate, using simulations generated by a computational model of amnesia, how the mechanism for this vulnerability to interference can be understood, not in terms of an impairment in encoding, storage or retrieval, but in terms of an impairment in encoding, storage and retrieval.

The representational–hierarchical view of amnesia: Translation from animal to human

Animal research has, in our opinion, made an invaluable contribution to our understanding of human amnesia. In this article we summarise our and others’ work in this area, focusing on a new view of amnesia we refer to as the representational–hierarchical view. According to this view—and in contrast to the prevailing paradigm in the field—the brain is best understood as a hierarchically organized continuum of representations, each of which is useful for a variety of cognitive functions. We focus our review on four visual discrimination paradigms that have been successfully translated into the human arena: configural concurrent discriminations, pair-wise “morph” discriminations, oddity discriminations, and configural oddity discriminations. The data from the animal studies are first reviewed, followed by illustrations of how the tasks have been utilized in human research. We then turn to the canonical impairment in animal models of amnesia, object recognition, and show how impairments in object recognition can be understood within the representational–hierarchical framework. This is followed by a discussion of predictions of the view related to classic issues in amnesia research, namely whether amnesia is due to a deficit of encoding, storage or retrieval, and the related issue of the role of interference in amnesia. Finally, we provide evidence from animal and human studies that even the hippocampus—almost universally regarded as a module for memory—may be better understood within the representational–hierarchical paradigm.

Developing an animal model of human amnesia: The role of the hippocampus

This review summarizes a series of experiments aimed at answering the question whether the hippocampus in rats can serve as an animal model of amnesia. It is recognized that a comparison of the functions of the rat hippocampus with human hippocampus is difficult, because of differences in methodology, differences in complexity of life experiences, and differences in the degree of hippocampal damage. Notwithstanding, rats and humans with hippocampal damage are similarly impaired on analogous tasks that assess spatial memory, spatial pattern separation, spatial configural and arbitrary associations, temporal order memory, temporal pattern separation, sequential learning, and temporal associations. These data suggest that the rat can serve as a model of memory dysfunction (amnesia) as it relates to spatial and temporal processing of new information.

An animal model of amnesia that uses Receiver Operating Characteristics (ROC) analysis to distinguish recollection from familiarity deficits in recognition memory

Here we review our development of an animal model of episodic memory and amnesia that employs a signal detection analyses to characterize recognition memory performance in rats. This approach aims to distinguish episodic recollection of studied items from mere familiarity for recently experienced stimuli, and then to examine the neural basis of these memory processes. Our findings on intact animals indicate that it is possible to distinguish independent components of recognition that are associated with features of recollection and familiarity in humans. Furthermore, we have found that damage limited to the hippocampus results in a selective deficit in recollection and not familiarity. Also, aging and prefrontal damage result in a similar pattern of impaired recollection and spared familiarity. However, whereas the recollection deficit following hippocampal damage can be attributed to the forgetting of studied materials, the impairment following prefrontal damage is due to false alarms, likely reflecting a deficit in source monitoring.

Cognitive effects of SL65.0155, a serotonin 5-HT 4 receptor partial agonist, in animal models of amnesia

Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT 4 receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT 4 receptors in different experimental models of amnesia in male Swiss mice or in male Sprague–Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of β-amyloid 1–42 fragment (BAP 1–42; 400 pmol/mouse) or of galanin (GAL) 1–29 (3 μg/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14 days, 15 min or 8 days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3 H)-one-monohydrochloride), a serotonin 5-HT 4 receptor partial agonist (1 mg/kg/day), for 7 days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1 mg/kg/day, i.p.) administered for 7 days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks.

P.5.027 Cognitive effects of SL650155, a 5HT4 receptor partial agonist, in animal models of amnesia

P.5.027 Cognitive effects of SL650155, a 5HT4 receptor partial agonist, in animal models of amnesia