Memory Deficits In Model Research Articles

Chromone hybrids as interleukin-6 and acetylcholinesterase inhibitor for treatment of Alzheimer's disease: Design, docking, synthesis and evaluation

The course of Alzheimer's disease (AD) is largely influenced by interleukin-6 (IL-6) and acetylcholinesterase (AChE). Therefore, concurrent suppression of these two targets is a rational approach for the development of anti-AD molecules. The study is aimed to design a molecule with pharmacophore capable of inhibiting both the targets. Four series are designed by coupling a chromone moiety (a pharmacophore that inhibits IL-6) with a N,N-disubstituted amine (that inhibits AChE) through a linker (1–4 carbon chain). The in silico studies on the designed compounds led to the identification of 16 best-fit compounds having good oral bioavailability and blood brain barrier permeability. All 16 compounds were synthesized and evaluated for anti-AChE activity. Six compounds showing >45 % inhibition of AChE at 1 μM concentration are further evaluated for BuChE (butyrylcholinesterase) and IL-6 inhibitory activities. Compound YS3g is the most potent inhibitor of EeAChE (IC50 = 0.45 μM) and of IL-6 (IC50 = 0.46 μM). Subsequently, it is found to show dose-dependent effects in STZ (streptozotocin)-induced memory deficit model at three doses (0.2, 0.4 and 0.8 mg/kg). At higher dose (0.8 mg/kg), it reverses the deficit as also supported by histopathological studies. The findings reveal that a chromone nucleus coupled with a piperazine via a three-carbon linker may be a useful template for developing novel moieties against AD.

Improvement of Cognitive Function by Fermented Panax ginseng C.A. Meyer Berries Extracts in an AF64A-Induced Memory Deficit Model.

This study investigated the potential therapeutic properties of fermented ginseng berry extract (GBE) for Alzheimer's disease (AD). Fermented GBE was examined for its ginsenoside content and physiological properties, which have been suggested to have neuroprotective effects and improve cognitive function. The results showed that fermented GBE contains high levels of major active ginsenosides and exhibits antioxidant and acetylcholinesterase inhibitory activities. Post-fermented GBE demonstrated therapeutic potential in AF64A-induced damaged neural stem cells and an animal model of AD. These findings suggest that fermented GBE may hold promise as a candidate for developing new therapeutic interventions for memory deficits and cognitive disorders associated with AD and other neurodegenerative conditions. However, further studies are needed to evaluate the safety, tolerability, and efficacy of fermented GBE in human subjects and to determine its clinical applications. In conclusion, our study provides evidence that fermented GBE has potential as a natural product for the prevention and treatment of AD. The high levels of active ginsenosides and antioxidant and acetylcholinesterase inhibitory activities of fermented GBE suggest that it may be a promising therapeutic agent for improving cognitive function and reducing neurodegeneration.

Cathepsin B Deficiency Improves Memory Deficits and Reduces Amyloid-β in hAβPP Mouse Models Representing the Major Sporadic Alzheimer's Disease Condition.

The lysosomal cysteine protease cathepsin B (CTSB) has been suggested as a biomarker for Alzheimer's disease (AD) because elevated serum CTSB in AD patients has been found to correlate with cognitive dysfunction. Furthermore, CTSB gene knockout (KO) in non-transgenic and transgenic AD animal models showed that elimination of CTSB improved memory deficits. However, conflicting CTSB KO results on amyloid-β (Aβ) pathology in transgenic AD models have been reported. The conflict is resolved here as likely being due to the different hAβPP transgenes used in the different AD mouse models. CTSB gene KO reduced wild-type (Wt) β-secretase activity, brain Aβ, pyroglutamate-Aβ, amyloid plaque, and memory deficits in models that used cDNA transgenes expressing hAβPP isoform 695. But in models that used mutated mini transgenes expressing hAβPP isoforms 751 and 770, CTSB KO had no effect on Wt β-secretase activity and slightly increased brain Aβ. All models expressed the AβPP transgenes in neurons. These conflicting results in Wt β-secretase activity models can be explained by hAβPP isoform specific cellular expression, proteolysis, and subcellular processing. CTSB KO had no effect on Swedish mutant (Swe) β-secretase activity in hAβPP695 and hAβPP751/770 models. Different proteolytic sensitivities for hAβPP with Wt versus Swe β-secretase site sequences may explain the different CTSB β-secretase effects in hAβPP695 models. But since the vast majority of sporadic AD patients have Wt β-secretase activity, the CTSB effects on Swe β-secretase activity are of little importance to the general AD population. As neurons naturally produce and process hAβPP isoform 695 and not the 751 and 770 isoforms, only the hAβPP695 Wt models mimic the natural neuronal hAβPP processing and Aβ production occurring in most AD patients. Significantly, these CTSB KO findings in the hAβPP695 Wt models demonstrate that CTSB participates in memory deficits and production of pyroglutamate-Aβ (pyroglu-Aβ), which provide rationale for future investigation of CTSB inhibitors in AD therapeutics development.

Expression of neurotransmitters, vasculogenesis markers and myosin heavy chain isoforms in the masseter muscle of senescence-accelerated mouse prone 8 mice.

Learning and memory deficits and pathologic changes in the hippocampus caused by toothlessness and soft diet feeding are related to reduced masseter muscle (MM) function. Myosin heavy chain (MyHC) isoform expression in the MM also changes under different chewing conditions. The neurotransmitter calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor A (VEGF-A) are involved in MM formation. However, the relationship between CGRP, VEGF-A and MyHC isoforms in the MM in the senescence-accelerated mouse prone 8 (SAMP8) strain, a model of learning and memory deficits, remains unclear. Changes in CGRP, VEGF-A, vasculogenesis marker, and MyHC isoform mRNA expression in the MMs of aging SAMP8 and senescence-accelerated mouse resistant 1 (SAMR1) mice was investigated through quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. qRT-PCR revealed obviously high CGRP levels in the SAMP8 mouse MM (p<0.001). MyHC-IId/x mRNA expression in the MM was higher in 24-week-old SAMP8 mice than 24-week-old SAMR1 mice (p<0.001) but lower in slow-MyHC SAMP8 mice than SAMR1 mice (p<0.001). CGRP mRNA was observed on the muscle fibers of the SAMP8 mouse MM but not the SAMR1 mouse MM through in situ hybridization. Principal component analysis (PCA) revealed strong positive contributions of SAMP8-MyHC-IId/x, SAMP8-CGRP, SAMR1-MyHC-emb, SAMR1-CGRP, SAMR1-VEGF-A, SAMR1-CD31, SAMP8-VEGF-A, and SAMP8-CD31 in the MM at 12 and 24 weeks. CGRP is also key for the MyHC-IId/x and slow-MyHC patterns in the MMs of SAMP8 mice.

Hizikia fusiforme functional oil (HFFO) prevents neuroinflammation and memory deficits evoked by lipopolysaccharide/aluminum trichloride in zebrafish.

BackgroundOxidative stress, cholinergic deficiency, and neuroinflammation are hallmarks of most neurodegenerative disorders (NDs). Lipids play an important role in brain development and proper functioning. Marine-derived lipids have shown good memory-improving potentials, especially those from fish and microalgae. The cultivated macroalga Hizikia fusiforme is healthy food and shows benefits to memory, but the study is rare on the brain healthy value of its oil. Previously, we had reported that the Hizikia fusiforme functional oil (HFFO) contains arachidonic acid, 11,14,17-eicosatrienoic acid, phytol, and other molecules displaying in vitro acetylcholinesterase inhibitory and nitroxide scavenging activity; however, the in vivo effect remains unclear. In this study, we further investigated its potential effects against lipopolysaccharides (LPS)- or aluminum trichloride (AlCl3)-induced memory deficiency in zebrafish and its drug-related properties in silica.MethodsWe established memory deficit models in zebrafish by intraperitoneal (i.p.) injection of lipopolysaccharides (LPS) (75 ng) or aluminum trichloride (AlCl3) (21 μg), and assessed their behaviors in the T-maze test. The interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), acetylcholine (ACh), and malondialdehyde (MDA) levels were measured 24 h after the LPS/AlCl3 injection as markers of inflammation, cholinergic activity, and oxidative stress. Furthermore, the interaction of two main components, 11,14,17-eicosatrienoic acid and phytol, was investigated by molecular docking, with the important anti-inflammatory targets nuclear factor kappa B (NF-κB) and cyclooxygenase 2 (COX-2). Specifically, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of HFFO were studied by ADMETlab.ResultsThe results showed that HFFO reduced cognitive deficits in zebrafish T-maze induced by LPS/AlCl3. While the LPS/AlCl3 treatment increased MDA content, lowered ACh levels in the zebrafish brain, and elevated levels of central and peripheral proinflammatory cytokines, these effects were reversed by 100 mg/kg HFFO except for MDA. Moreover, 11,14,17-eicosatrienoic acid and phytol showed a good affinity with NF-κB, COX-2, and HFFO exhibited acceptable drug-likeness and ADMET profiles in general.ConclusionCollectively, this study's findings suggest HFFO as a potent neuroprotectant, potentially valuable for the prevention of memory impairment caused by cholinergic deficiency and neuroinflammation.

Soluble guanylate cyclase stimulator riociguat improves spatial memory in mice via peripheral mechanisms

Soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signalling is important for healthy memory function and a healthy vascular system. Targeting sGC-cGMP signalling can therefore be a potential strategy to enhance memory processes. sGC can be targeted by using agonists, such as sGC stimulator riociguat. Therefore, this study aimed to target sGC using riociguat to investigate its acute effects on memory function and neuronal plasticity in mice. The effects of riociguat on long-term memory and a biperiden-induced memory deficit model for assessing short-term memory were tested in the object location task, and working memory was tested in the Y-maze continuous alternation task. Pharmacokinetic measurements were performed within brain tissue of mice, and hippocampal plasticity measures were assessed using western blotting. Acute oral administration with a low dose of 0.03 mg/kg riociguat was able to enhance working-, short-, and long-term spatial memory. Under cerebral vasoconstriction higher doses of riociguat were still effective on memory. Pharmacokinetic measurements revealed poor brain penetration of riociguat and its metabolite M−1. Increased activation of VASP was found, while no effects were found on other memory-related hippocampal plasticity measures. Memory enhancing effects of riociguat are most likely regulated by vascular peripheral effects on cGMP signalling. Yet, further research is needed to investigate the possible contribution of hemodynamic or metabolic effects of sGC stimulators on memory performance.

Multitarget Effect of 2-(4-(Methylthio)phenyl)-3-(3-(piperidin-1-yl)propyl)thiazolidin-4-one in a Scopolamine-Induced Amnesic Rat Model.

Cholinergic system dysfunction, oxidative damage, and alterations in ion pump activity have been associated with memory loss and cognitive deficits in Alzheimer's disease. 1,3-thiazolidin-4-ones have emerged as a class of compounds with potential therapeutic effects due to their potent anticholinesterase activity. Accordingly, this study investigated the effect of the 2-(4-(methylthio)phenyl)-3-(3-(piperidin-1-yl)propyl)thiazolidin-4-one (DS12) compound on memory, cholinergic and oxidative stress parameters, ion pump activity, and serum biochemical markers in a scopolamine-induced memory deficit model. Male Wistar rats were divided into four groups: I-Control; II-Scopolamine; III-DS12 (5mg/kg) + scopolamine; and IV-DS12 (10mg/kg) + scopolamine. The animals from groups III and IV received DS12 diluted in canola oil and administered for 7days by gavage. On the last day of treatment, scopolamine (1mg/kg) was administered intraperitoneally (i.p.) 30min after training in an inhibitory avoidance apparatus. Twenty-four hours after scopolamine administration, the animals were subjected to an inhibitory avoidance test and were thereafter euthanized. Scopolamine induced memory deficits, increased acetylcholinesterase activity and oxidative damage, and decreased Na+/K+-ATPase activity in cerebral cortex and hippocampus. Pretreatment with DS12 prevented these brain alterations. Scopolamine also induced an increase in acetylcholinesterase activity in lymphocytes and whereas butyrylcholinesterase in serum and treatment with DS12 prevented these changes. In animals treated with DS12, no changes were observed in renal and hepatic parameters when compared to the control group. In conclusion, DS12 emerged as an important multitarget compound capable of preventing neurochemical changes associated with memory deficits.

Neuroprotective potential of methanolic extract of Saraca asoca bark against doxorubicin-induced neurotoxicity

Background: Doxorubicin (DOX) is a widely used anthracycline-based anticancer agent, which causes a gradual decline in cognition on long-term usage in breast cancer patients that affect their quality of life negatively. Aim: The present study was designed to assess the neuroprotective potential of Saraca asoca bark against Dox-induced neurotoxicity, considering its previously reported anticlastogenic effect. Materials and Methods: Methanolic extract of bark was prepared by Soxhlet extraction and characterized by high-performance thin-layer chromatography (catechin-8.82%). In vitro studies were performed in IMR-32 neuroblastoma cells using cell viability and neurite growth assay to determine the neuroprotective potential of the extract against DOX-induced neurotoxicity. In vivo neuroprotection study of extract (100 and 200 mg/kg p. o) was performed by assessing episodic memory through novel object recognition test (NORT) in DOX-induced (10 cycles, 2.5 mg/kg, 5 days apart) memory deficit model. In addition, antioxidant markers and acetylcholinesterase activity in hippocampus and frontal cortex were evaluated. Results and Conclusion: The extract showed significant in vitro neuroprotection toward differentiated cells in morphological features and cell viability assessment against DOX (IC50-63.35 and 45.17 μg/ml against 1 μg/ml and 2 μg/ml DOX, respectively, and 0.46 μg/ml for DOX alone in 3-[4,5 dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay). DOX-treated animals showed depletion in episodic memory while extract at 100 mg/kg significantly prevented it. Similar changes were observed in antioxidant markers levels in the brain. DOX treatment elevated acetylcholinesterase activity which was significantly reversed by the treatment with extract. Thus, it can be stated that the neuroprotective and antioxidant potentials of extract possibly underlie the efficacy against the DOX-induced neurotoxicity. Abbreviations Used: DOX: Doxorubicin; S. asoca: Saraca asoca; DMEM: Dulbecco's Modified Eagle's Medium (DMEM); MTT: 3-[4,5 dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide; FBS: Fetal bovine serum; RA: Retinoic acid; CMC: Carboxymethyl cellulose; SOD: Superoxide dismutase; GSH: Reduced glutathione; HPTLC: High-performance thin-layer chromatography; NORT: Novel object recognition task; ITI: Intertrial interval; MPO: Myeloperoxidase; MDA: Malondialdehyde; RI: Recognition index; DI: Discrimination index.

N-(p-amylcinnamoyl) anthranilic acid attenuates remedial effects of memantine on memory deficits following intracerebroventricular streptozotocin administration in rats.

N-(p-amylcinnamoyl) anthranilic acid (ACA) is a blocker of transient receptor potential melastatin-2 (TRPM2) which is a non-selective, Ca2+-permeable and oxidative stress sensor cation channel. Intracerebroventricular (ICV) streptozotocin (STZ) induction successfully generates spatial memory deficits in rats. The purpose of this study was to investigate effects of ACA on a rat model of STZ-induced learning and memory deficits. A total of 60 Wistar rats randomly divided into six groups; (1) control, (2) sham-operated, (3) ICV-STZ administered, (4) ICV-STZ + memantine (5 mg/kg i.p.), (5) ICV-STZ + ACA (25 mg/kg i.p.) and (6) a combination therapy group, ICV-STZ + ACA (25 mg/kg) + memantine (5 mg/kg). Effects of the drugs on spatial memory deficits were appraised in Morris water maze (MWM) apparatus. Anxiety-like behavior of the rats were also assessed by using both the elevated plus maze (EPM) and open field maze (OFM) apparatuses. Western blot analysis of hippocampal tissues revealed TRPM2-L channel protein expression levels. Serum levels of tumor necrosis factor alpha (TNF-α) and malondialdehyde (MDA) were detected by enzyme-linked immunosorbent assay (ELISA) kits. Memantine treatment ameliorated the spatial memory deficits induced, as evidenced by the MWM tests. However, ACA treatment did not provide any improvement, instead positive effects of memantine were attenuated by ACA treatment. Western blot analysis in hippocampal tissues showed that TRPM2-L protein expression was markedly suppressed in ICV-STZ administered group. The ACA treatment reversed that suppression. Surprisingly, the memantine treatment resulted in overexpression of TRPM2-L, to a certain extent. Examination of the rats in EPM and OFM apparatuses, as a display of anxiety-like behavior, did not reveal any marked difference among groups. Serum levels of TNF-α and MDA also did not vary significantly among groups, as well. Conclusively, our findings showed for the first time that TRPM2-L protein expression was significantly suppressed in the ICV-STZ induced memory deficit model. Even though ACA reversed this suppression, no improvement in spatial memory was observed following ACA treatment.

CGY-1, a biflavonoid isolated from cardiocrinum giganteum seeds, improves memory deficits by modulating the cholinergic system in scopolamine-treated mice

Certain biflavonoids have been proven to protect against cognitive dysfunction. A new biflavonoid, CGY-1, isolated from Cardiocrinum giganteum seeds, has not yet been reported to have any neuroprotective effect. In this study, a scopolamine-induced memory deficit model was used to explore the neuroprotective effect of CGY-1. Behavioral experiments, such as tests using the Morris water maze, the Y-maze and the fear conditioning test, were conducted. The results revealed that oral administration of CGY-1 (20 and 40 mg/kg) and donepezil shortened the escape latency, improved the percentage of spontaneous alternation, and increased the freezing times, respectively. CGY-1 decreased the levels of reactive oxygen species and malondialdehyde and increased the activities of superoxide dismutase and glutathione peroxidase in the hippocampus. In addition, CGY-1 decreased the activity of acetylcholinesterase and increased the activities of choline acetyltransferase and acetylcholine in the hippocampus. Furthermore, qPCR and western blot results revealed that the expressions of neurotrophic factors, brain-derived neurotrophic factor and nerve growth factor were upregulated in the hippocampus after CGY-1 treatment. In conclusion, CGY-1 could be a promising candidate for the treatment of cognitive dysfunction.

Commentary on Some Recent Theses Relevant to Combating Aging: October 2018.

Theses reviewed in this issue include "Computational Pathology for Quantifying Spatial Heterogeneity in Digital Images of Tissue Sections from Solid Tumors," "Molecular Analysis of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Brain Tissue Identifies Disease Mechanisms Associated with Repetitive DNA Elements," "Neuroprotective Potential of the N-Terminal Beta Amyloid Peptide Fragment in the Neurodegeneration, Synaptic Dysfunction and Memory Deficits in Models of Alzheimer's Disease," "pH-triggered Self-Assembly of a PEGylated Peptide Amphiphilic Contrast Agent," "Quantitative Approaches for Profiling the T Cell Receptor Repertoire in Human Tissues," and "Regulation and Repair of Neural Stem Cells and the Neurogenic Niche."

Jiao-Tai-Wan Improves Cognitive Dysfunctions through Cholinergic Pathway in Scopolamine-Treated Mice.

Cognitive dysfunction is characterized as the gradual loss of learning ability and cognitive function, as well as memory impairment. Jiao-tai-wan (JTW), a Chinese medicine prescription including Coptis chinensis and cinnamon, is mainly used for the treatment of insomnia, while the effect of JTW in improving cognitive function has not been reported. In this study, we employed a scopolamine- (SCOP-) treated learning and memory deficit model to explore whether JTW could alleviate cognitive dysfunction. In behavioral experiments, Morris water maze, Y-maze, fearing condition test, and novel object discrimination test were conducted. Results showed that oral administration of JTW (2.1 g/kg, 4.2 g/kg, and 8.4 g/kg) can effectively promote the ability of spatial recognition, learning and memory, and the memory ability of fresh things of SCOP-treated mice. In addition, the activity of acetylcholinesterase (AChE) was effectively decreased; the activity of choline acetyltransferase (ChAT) and concentration of acetylcholine (Ach) were improved after JTW treatment in both hippocampus and cortex of SCOP-treated mice. JTW effectively ameliorated oxidative stress because of decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and increased the activities of superoxide dismutase (SOD) and catalase (CAT) in hippocampus and cortex. Furthermore, JTW promotes the expressions of neurotrophic factors including postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) and brain-derived neurotrophic factor (BDNF) in both hippocampus and cortex. Nissl's staining shows that the neuroprotective effect of JTW was very effective. To sum up, JTW might be a promising candidate for the treatment of cognitive dysfunction.

Catechin ameliorates doxorubicin-induced neuronal cytotoxicity in in vitro and episodic memory deficit in in vivo in Wistar rats.

Cognitive dysfunction by chemotherapy compromises the quality of life in cancer patients. Tea polyphenols are known chemopreventive agents. The present study was designed to evaluate the neuroprotective potential of (+) catechin hydrate (catechin), a tea polyphenol, in IMR-32 neuroblastoma cells in vitro and alleviation of episodic memory deficit in Wistar rats in vivo against a widely used chemotherapeutic agent, Doxorubicin (DOX). In vitro, neuroprotective studies were assessed in undifferentiated IMR-32 cells using percentage viability and in differentiated cells by neurite length. These studies showed catechin increased percentage viability of undifferentiated IMR-32 cells. Catechin pretreatment also showed an increase in neurite length of differentiated cells. In vivo neuroprotection of catechin was evaluated using novel object recognition task in time-induced memory deficit model at 50, 100 and 200mg/kg dose and DOX-induced memory deficit models at 100mg/kg dose. The latter model was developed by injection of DOX (2.5mg/kg, i.p.) in 10 cycles over 50days in Wistar rats. Catechin showed a significant reversal of time-induced memory deficit in a dose-dependent manner and prevention of DOX-induced memory deficit at 100mg/kg. In addition, catechin treatment showed a significant decrease in oxidative stress, acetylcholine esterase and neuroinflammation in the hippocampus and cerebral cortex in DOX-induced toxicity model. Hence, catechin may be a potential adjuvant therapy for the amelioration of DOX-induced cognitive impairment which may improve the quality of life of cancer survivors. This improvement might be due to the elevation of antioxidant defense, prevention of neuroinflammation and inhibition of acetylcholine esterase enzyme.

Effects of Non-Spatial Pre-Training on Learning and Memory Impairment Detection in the Morris Water Maze

One of the most popular learning and memory tests is the Morris water maze. The Morris water maze is a circular pool filled with water with a hidden platform under the water surface. The test is appropriate for rodents, especially rats and mice. The testing protocol comprises 2 parts that evaluate learning ability and memory retention. When animals are placed in the pool, they experience stress, which is the driving force for discovery of a strategy to leave the water. In the experiment, animals use environmental cues to find the location of the hidden platform in the pool. After consecutive training days, animals can more quickly locate the hidden platform. The last day of the task involves a memory test without the platform. It shows a limitation of the test in mild learning and memory deficit models such as 2-vessel occlusion. Differences between the normal and memory impairment models are expressed only in a narrow range. So, we tried to modify the original protocol for mild learning and memory impairment models. We used an albino rat strain for the experiment. A pre-training strategy of 3 days of swimming in the pool with a visible platform prior to the ordinary task was used. The results suggest that this pre-training strategy improved learning and memory in the rat model. When compared to normal rats and 2-vessel occlusion rats (a rat model for vascular dementia), those that participated in the pre-training strategy showed an increase in the percent difference of area under the curve for learning trials. In conclusion, the pre-training strategy increases ability to discriminate learning and memory impairment in the rat model, especially for the mild learning and memory deficit models.

Differential metformin dose-dependent effects on cognition in rats: role of Akt.

Epidemiological evidence suggests that individuals with diabetes mellitus are at greater risk of developing Alzheimer's disease, and controversy overwhelms the usefulness of the widely prescribed insulin-sensitizing drug, metformin, on cognition. Through the scopolamine-induced memory deficit model, we investigated metformin influence on cognitive dysfunction and explored underlying mechanisms. Sixty adult male Wistar rats were randomly assigned into 5 groups (12 rats each) to receive either normal saline, scopolamine 1mg/kg intraperitoneally once daily, scopolamine + oral metformin (100mg/kg/day), scopolamine + oral metformin (300mg/kg/day) or scopolamine + oral rivastigmine (0.75mg/kg/day) for 14days. Cognitive behaviours were tested using Morris water maze and passive avoidance tasks. Biochemically, brain oxidative (malondialdehyde) and inflammatory (TNF-α) markers, nitric oxide, Akt, phospho-Akt, phospho-tau and acetyl cholinesterase activity in hippocampal and cortical tissues were assessed. The lower dose of metformin (100mg/kg) ameliorated scopolamine-induced impaired performance in both Morris water maze and passive avoidance tasks, and was associated with significant reduction of inflammation and to a lesser extent oxidative stress versus rivastigmine. Given the role of total Akt in regulation of abnormal tau accumulation and degradation, our finding that metformin 100 decreased the elevated total Akt while increasing its phosphorylated form explains its beneficial modulatory effect on phosphorylated tau in both tissues, and could further clarify its protection against memory impairment. Metformin, only in the average human antidiabetic dose, offers a protective effect against scopolamine-induced cognitive impairment, while no deleterious effect was observed with the higher dose, which may support a bonus effect of metformin in type 2 diabetic patients.

Compound Reverses Memory Deficits in Model of Schizophrenia

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Naringin and Rutin Alleviates Episodic Memory Deficits in Two Differentially Challenged Object Recognition Tasks.

Background:Cognitive decline or dementia is a debilitating problem of neurological disorders such as Alzheimer's and Parkinson's disease, including special conditions like chemobrain. Dietary flavonoids proved to be efficacious in delaying the incidence of neurodegenerative diseases. Two such flavonoids, naringin (NAR) and rutin (RUT) were reported to have neuroprotective potential with beneficial effects on spatial and emotional memories in particular. However, the efficacy of these flavonoids is poorly understood on episodic memory, which comprises an important form of autobiographical memory.Objective:This study objective is to evaluate NAR and RUT to reverse time-delay-induced long-term and scopolamine-induced short-term episodic memory deficits in Wistar rats.Materials and Methods:We have evaluated both short-term and long-term episodic memory forms using novel object recognition task. Open field paradigm was used to assess locomotor activity for any confounding influence on memory assessment. Donepezil was used as positive control and was effective in both models at 1 mg/kg, i.p.Results:Animals treated with NAR and RUT at 50 and 100 mg/kg, p.o. spent significantly more time exploring novel object compared to familiar one, whereas control animals spent almost equal time with both objects in choice trial. NAR and RUT dose-dependently increased recognition and discriminative indices in time-induced long-term as well as scopolamine-induced short-term episodic memory deficit models without interfering with the locomotor activity.Conclusion:We conclude that, NAR and RUT averted both short- and long-term episodic memory deficits in Wistar rats, which may be potential interventions for neurodegenerative diseases as well as chemobrain condition.SUMMARY Incidence of Alzheimer's disease is increasing globally and the current therapy is only symptomatic. Curative treatment is a major lacuna. NAR and RUT are natural flavonoids proven for their pleiotropic pharmacological effects with potential neuroprotective benefits. The study evaluated these flavonoids for their potential to improve the most common form of episodic memory (memory of autobiographical events in relation to time, places etc.) in two differential animal models assessing short-term and long-term memory, respectively. We also found that NAR and RUT were able to reverse both short-term and long-term memory deficits dose dependently in female Wistar rats. Abbreviations used: AD: Alzheimer's disease, AChE: Acetylcholinesterase, COX: Cyclooxygenase, DI: Discriminative index, ITI: Inter trial interval, NAR: Naringin, RUT: Rutin, NORT: Novel object recognition task, NOS: Nitric oxide synthase, QOL: Quality of life, RI: Recognition index, WFI: Water for injection

A laboratory quest on use of date fruit (Phoenix Dactylifera, L) extract in prevention of chemically induced memory deficit models in mice

Background:Alzheimer’s disease (AD) is affecting approximately 46 million people worldwide. Date fruits (Phoenix dactylifera L.) are important fruits which have been cultivated in the Middle East for over 6000 years or more. For the native arabs, dates are an integral part of food. They possess many useful properties such as antioxidant, neuroprotective, anti stress and anticholesteromic which are essential for an effective Antialzheimer drug. Hence, based on above observations we hypothesize that date fruits can offer potential benefits for the treatment/prevention of AD. Methods: Scopolamine and streptozotocin were used to induce memory loss in experimental mice. The prepared aqueous extract was analyzed for various chemical constituents by using standardized methods. Its antioxidant activity was established using DPPH free radical method. Scopolamine and streptozotocin were used to induce memory deficit. Different doses of the extract such as 100, 200 and 400 mg/kg were selected for the study. The potential of the extract in exhibiting nootropic activity was explored by using elevated plus maze in mice treated with the extract for a period of 30 days. At the end of treatment period and I hour after last dose, the transfer latency was recorded. In order to analyze the retention of this learned-task, the transfer latency was recorded again 24 h later. The effect of the extract in reversing scopolamine and streptozotocin was also carried. Results: The results of in vitro tests proved that DFE to be an antioxidant whereas in vivo study indicated DFE had nootropic activity in absence of cognitive deficit and was also successful in preventing the chemically induced memory deficits in experimental mice. The mechanism by which DFE showed these effects could be attributed to its antioxidant, neuroprotective properties, its choline content or activation of acetylcholine system in brain. Conclusions: In the light of above, it may be worthwhile to explore the potential of this fruit in the management of Alzheimer’s disease patients.

The relationship between neuropsychological functioning and FDG-PET hypometabolism in intractable mesial temporal lobe epilepsy

We examined the relationship between baseline neuropsychological functioning and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) in intractable mesial temporal lobe epilepsy (MTLE). We hypothesized relationships between dominant temporal lobe hypometabolism and verbal memory and between nondominant temporal lobe hypometabolism and nonverbal memory in line with the lateralized material-specific model of memory deficits in MTLE. We also hypothesized an association between performance on frontal lobe neuropsychological tests and prefrontal hypometabolism. Thirty-two patients who had undergone temporal lobectomy for treatment of MTLE and who completed both presurgical FDG-PET and comprehensive neuropsychological investigations with widely used standardized measures were included. Age-adjusted composite measures were calculated for verbal memory, nonverbal memory, relative material-specific memory, IQ, executive function, attention/working memory, and psychomotor speed. Fluorodeoxyglucose positron emission tomography was analyzed with statistical parametric mapping (SPM) to identify hypometabolism relative to healthy controls. Pearson's correlation was used to determine the relationship between regions of hypometabolism and neuropsychological functioning. Dominant temporal lobe hypometabolism was associated with relatively inferior verbal memory, while nondominant temporal lobe hypometabolism was associated with inferior nonverbal memory. No relationship was found between performance on any frontal lobe measures and prefrontal hypometabolism. Statistical parametric mapping-quantified lateralized temporal lobe hypometabolism correlates with material-specific episodic memory impairment in MTLE. In contrast, prefrontal hypometabolism is not associated with performance on frontal lobe measures. We suggest that this is because frontal lobe neuropsychology tests may not be good measures of isolated frontal lobe functioning.

Ginger improves cognitive function via NGF-induced ERK/CREB activation in the hippocampus of the mouse

Ginger (the rhizome of Zingiber officinale Roscoe) has been used worldwide for many centuries in cooking and for treatment of several diseases. The main pharmacological properties of ginger include anti-inflammatory, antihyperglycemic, antiarthritic, antiemetic and neuroprotective actions. Recent studies demonstrated that ginger significantly enhances cognitive function in various cognitive disorders as well as in healthy brain. However, the biochemical mechanisms underlying the ginger-mediated enhancement of cognition have not yet been studied in normal or diseased brain. In the present study, we assessed the memory-enhancing effects of dried ginger extract (GE) in a model of scopolamine-induced memory deficits and in normal animals by performing a novel object recognition test. We found that GE administration significantly improved the ability of mice to recognize novel objects, indicating improvements in learning and memory. Furthermore, to elucidate the mechanisms of GE-mediated cognitive enhancement, we focused on nerve growth factor (NGF)-induced signaling pathways. NGF enzyme-linked immunosorbent assay analysis revealed that GE administration led to elevated NGF levels in both the mouse hippocampus and rat glioma C6 cells. GE administration also resulted in phosphorylation of extracellular-signal-regulated kinase (ERK) and cyclic AMP response element-binding protein (CREB), as revealed by Western blotting analysis. Neutralization of NGF with a specific NGF antibody inhibited GE-triggered activation of ERK and CREB in the hippocampus. Also, GE treatment significantly increased pre- and postsynaptic markers, synaptophysin and PSD-95, which are related to synapse formation in the brain. These data suggest that GE has a synaptogenic effect via NGF-induced ERK/CREB activation, resulting in memory enhancement.