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  1. Fulltext Protective effects of Centella asiatica extract on spatial memory and learning deficits in animal model of systemic inflammation induced by lipopolysaccharide
    Md Pisar M, Chee BJ, Long I, Osman A
    Ann Med, 2023 Dec;55(1):2224970.
    PMID: 37318144 DOI: 10.1080/07853890.2023.2224970
    BACKGROUND AND AIM: Centella asiatica (L.) Urb. (Apiaceae) is a renowned medicinal plant being used in the Ayurvedic system for its pharmacological effects on the central nervous system such as rejuvenating, sedative, anxiolytic and memory-enhancing properties. The present study was designed to investigate the effect of Centella asiatica (CA) extract on inflammatory responses induced by lipopolysaccharide (LPS) and resulting changes in cognitive behavior.

    MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into 4 groups as control, LPS, CA and LPS + CA. The treatments with LPS (5 mg/kg) were intraperitoneally (i.p) injected on day 4 and CA ethanol extract (200 mg/kg) were given orally for 14 days. Morris Water Maze (MWM) test was performed to assess spatial learning and memory performance. Acute oral toxicity of the extract at the highest dose of 5000 mg/kg was also conducted.

    RESULTS: Single administration of LPS was able to significantly elicit learning and memory impairment (p spatial memory at the time point of study.The study showed that the learning capability during the training trial was restored or ameliorated with the pre-emptive treatment of Centella asiatica extract (200 mg/kg).Centella asiatica extract improves spatial memory, learning deficits and regulates proinflammatory responses in systemic LPS-treated rats.

    Matched MeSH terms: Spatial Memory*
  2. TRPM4 inhibition improves spatial memory impairment and hippocampal long-term potentiation deficit in chronic cerebral hypoperfused rats
    Hazalin NAMN, Liao P, Hassan Z
    Behav Brain Res, 2020 09 01;393:112781.
    PMID: 32619565 DOI: 10.1016/j.bbr.2020.112781
    Chronic cerebral hypoperfusion (CCH) been well characterized as a common pathological status contributing to neurodegenerative diseases such as Alzheimer's disease and vascular dementia. CCH is an important factor that leads to cognitive impairment, but the underlying neurobiological mechanism is poorly understood and no effective treatment is available. Recently, transient receptor potential melastatin 4 (TRPM4) cation channel has been identified as an important molecular element in focal cerebral ischemia. Over activation of the channel is a major molecular mechanism of oncotic cell death. However, the role of TRPM4 in CCH that propagates global brain hypoxia have not been explored. Therefore, the present study is designed to investigate the effect of TRPM4 inhibition on the cognitive functions of the rats following CCH via permanent bilateral occlusion of common carotid arteries (PBOCCA) model. In this model, treatment with siRNA suppressed TRPM4 expression at both the mRNA and protein levels and improved cognitive deficits of the CCH rats without affecting their motor function. Furthermore, treatment with siRNA rescued the LTP impairment in CCH-induced rats. Consistent with the restored of LTP, western blot analysis revealed that siRNA treatment prevented the reduction of synaptic proteins, including calcium/calmodulin-dependent kinase II alpha (CaMKIIα) and brain-derived neurotrophic factor (BDNF) in brain regions of CCH rats. The present findings provide a novel role of TRPM4 in restricting cognitive functions in CCH and suggest inhibiting TRPM4 may represent a promising therapeutic strategy in targeting ion channels to prevent the progression of cognitive deficits induced by ischemia.
    Matched MeSH terms: Spatial Memory/physiology*
  3. Fulltext Differential expression of entorhinal cortex and hippocampal subfields α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica
    Wong JH, Muthuraju S, Reza F, Senik MH, Zhang J, Mohd Yusuf Yeo NAB, et al.
    Biomed Pharmacother, 2019 Feb;110:168-180.
    PMID: 30469081 DOI: 10.1016/j.biopha.2018.11.044
    Centella asiatica (CA) is a widely used traditional herb, notably for its cognitive enhancing effect and potential to increase synaptogenesis. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) mediate fast excitatory neurotransmission with key roles in long-term potentiation which is believed to be the cellular mechanism of learning and memory. Improved learning and memory can be an indication to the surface expression level of these receptors. Our previous study demonstrated that administration of CA extract improved learning and memory and enhanced expression of AMPAR GluA1 subunit while exerting no significant effects on GABAA receptors of the hippocampus in rats. Hence, to further elucidate the effects of CA, this study investigated the effects of CA extract in recognition memory and spatial memory, and its effects on AMPAR GluA1 and GluA2 subunit and NMDAR GluN2 A and GluN2B subunit expression in the entorhinal cortex (EC) and hippocampal subfields CA1 and CA3. The animals were administered with saline, 100 mg/kg, 300 mg/kg, and 600 mg/kg of CA extract through oral gavage for 14 days, followed by behavioural analysis through Open Field Test (OFT), Novel Object Recognition Task (NORT), and Morris Water Maze (MWM) and lastly morphological and immunohistochemical analysis of the surface expression of AMPAR and NMDAR subunits were performed. The results showed that 14 days of administration of 600 mg/kg of CA extract significantly improved memory assessed through NORT while 300 mg/kg of CA extract significantly improved memory of the animals assessed through MWM. Immunohistochemical analysis revealed differential modulation effects on the expressions of receptor subunits across CA1, CA3 and EC. The CA extract at the highest dose (600 mg/kg) significantly enhanced the expression of AMPAR subunit GluA1 and GluA2 in CA1, CA3 and EC, and NMDAR subunit GluN2B in CA1 and CA3 compared to control. At 300 mg/kg, CA significantly increased expression of AMPAR GluA1 in CA1 and EC, and GluA2 in CA1, CA3 and EC while 100 mg/kg of CA significantly increased expression of only AMPAR subunit GluA2 in CA3 and EC. Expression of NMDAR subunit GluN2 A was significantly reduced in the CA3 (at 100, 300, and 600 mg/kg) while no significant changes of subunit expression was observed in CA1 and EC compared to control. The results suggest that the enhanced learning and memory observed in animals administered with CA was mainly mediated through increased expression of AMPAR GluA1 and GluA2 subunits and differential expression of NMDAR GluN2 A and GluN2B subunits in the hippocampal subfields and EC. With these findings, the study revealed a new aspect of cognitive enhancing effect of CA and its therapeutic potentials through modulating receptor subunit expression.
    Matched MeSH terms: Spatial Memory/drug effects*; Spatial Memory/physiology
  4. Activation of sphingosine 1-phosphate receptor-1 by SEW2871 improves cognitive function in Alzheimer's disease model rats
    Asle-Rousta M, Oryan S, Ahmadiani A, Rahnema M
    EXCLI J, 2013;12:449-61.
    PMID: 26417237
    Sphingosine-1 phosphate (S1P) is involved in a variety of cellular processes via activation of S1P receptors (S1PRs; S1PR1 to S1PR5) that are highly expressed in the brain. It has been shown that the level of S1P is reduced in the brain of Alzheimer's disease (AD) patients. However, there is no study designed to evaluate the expression of S1PRs in AD brains. The objectives of the present work are (1) to examine the expression of S1PR1-3 in the hippocampus of beta amyloid (Aβ) 1-42 injected rats and (2) to clarify the effects of chronic S1PR1 activation on S1PR1-3 levels, spatial memory deficit and hippocampal damage in AD rats. SEW2871, the S1PR1 selective agonist, repeatedly was injected intraperitoneally during a period of two weeks. Upon Western Blot data bilateral intrahippocampal injection of Aβ1-42 decreased the expression of S1PR1 while increased S1PR2 level and did not affect that of S1PR3. We found that chronic administration of SEW2871 inhibited the reduction of S1PR1 expression and ameliorated spatial memory impairment in the Morris water maze task in rats. In addition, SEW2871 attenuated the Aβ1-42-induced hippocampal neuronal loss according to Nissl staining findings. Data in the current study highlights the importance of S1PR1 signaling pathway deregulation in AD development and suggests that activation of S1PR1 may represent a potential approach for developing new therapeutics to manage memory deficit and apoptosis associated with neurodegenerative disorders such as AD.
    Matched MeSH terms: Spatial Memory
  5. Fulltext Neuronal Cell Death and Mouse (Mus musculus) Behaviour Induced by Bee Venom
    Oktiansyah R, Juliandi B, Widayati KA, Juniantito V
    Trop Life Sci Res, 2018 Jul;29(2):1-11.
    PMID: 30112137 DOI: 10.21315/tlsr2018.29.2.1
    Neuronal cell death can occur in a tissue or organ, including the brain, which affects memory. The objectives of this study were to determine the dose of bee venom that causes neuronal death and analyse the alteration of mouse behaviour, focusing in particular on spatial memory. Fifteen male mice of Deutsche Denken Yoken (DDY) strain were divided into control and treatment groups. Bee venom was injected six times for two weeks intraperitoneally with 1.88 mg/kg, 3.76 mg/kg, 5.6 mg/kg, and 7.48 mg/kg doses of venom. Brain histology was studied using haematoxylin-eosin stained paraffin embedded 5 μm coronal sections. A Y maze test was used to assay behaviour. Parameters observed were the number of dead neurons and the percentage of mice with altered behaviour. ANOVA showed that the effects of bee venom were significantly different in the case of the neuronal death parameter but were not significantly different in the case of the mice behaviour parameter. Duncan's Multiple Range Test (DMRT) demonstrated that P4 (7.48 mg/kg) gave the highest effect of bee venom to promote neuronal death.
    Matched MeSH terms: Spatial Memory
  6. Fulltext Phencyclidine dose optimisation for induction of spatial learning and memory deficits related to schizophrenia in C57BL/6 mice
    Zain MA, Rouhollahi E, Pandy V, Mani V, Majeed ABA, Wong WF, et al.
    Exp Anim, 2018 Nov 01;67(4):421-429.
    PMID: 29731492 DOI: 10.1538/expanim.18-0006
    Phencyclidine (PCP) has been used to model cognitive deficits related to schizophrenia in rats and mice. However, the model in mice is not consistent in terms of the PCP effective dose reported. Furthermore, most of the previous studies in mice excluded the presence of drug washout period in the regime. Thus, we aimed to optimize the dose of PCP in producing robust cognitive deficits by implementing it in a PCP regime which incorporates a drug washout period. The regimen used was 7 days' daily injection of PCP or saline for treatment and vehicle groups, respectively; followed by 24 h drug washout period. After the washout period, the test mice were tested in water maze (5 days of acquisition + 1 day of probe trial) for assessment of spatial learning and memory. Initially, we investigated the effect of PCP at 2mg/kg, however, no apparent impairment in spatial learning and memory was observed. Subsequently, we examined the effect of higher doses of PCP at 5, 10 and 20 mg/kg. We found that the PCP at 10 mg/kg produced a significant increase in "latency to reach the platform" during the acquisition days and a significant increase in "latency of first entry to previous platform" during the probe day. There was no significant change observed in "swim speed" during the test days. Thus, we concluded that PCP at 10 mg/kg produced robust deficits in spatial learning and memory without being confounded by motor disturbances.
    Matched MeSH terms: Spatial Memory/drug effects*
  7. Virgin Coconut Oil-Induced Neuroprotection in Lipopolysaccharide-Challenged Rats is Mediated, in Part, Through Cholinergic, Anti-Oxidative and Anti-Inflammatory Pathways
    Rahim NS, Lim SM, Mani V, Hazalin NAMN, Majeed ABA, Ramasamy K
    J Diet Suppl, 2020 Oct 14.
    PMID: 33962540 DOI: 10.1080/19390211.2020.1830223
    Neuroinflammation is associated with neuronal cell death and could lead to chronic neurodegeneration. This study investigated the neuroprotective potential of virgin coconut oil (VCO) against lipopolysaccharide (LPS)-induced cytotoxicity of neuroblastoma SK-N-SH cells. The findings were validated using Wistar rats, which were fed with 1-10 g/kg VCO for 31 days, exposed to LPS (0.25 mg/kg) and subjected to the Morris Water Maze Test. Brain homogenate was subjected to biochemical analyses and gene expression studies. α-Tocopherol (α-T; 150 mg/kg) served as the positive control. VCO (100 µg/mL) significantly (p spatial memory of LPS-challenged rats. Brain homogenate of VCO-fed rats was presented with increased acetylcholine (+33%) and reduced acetylcholinesterase (-43%). The upregulated antioxidants may have reduced neuroinflammation [malondialdehyde (-51%), nitric oxide (-49%), Cox-2 (-64%) and iNos (-63%)] through upregulation of IL-10 (+30%) and downregulation of IL-1β (-65%) and Interferon-γ (-25%). There was also reduced expression of Bace-1 (-77%). VCO-induced neuroprotection, which was comparable to α-T, could be mediated, in part, through inflammatory, cholinergic and amyloidogenic pathways.
    Matched MeSH terms: Spatial Memory
  8. Phyllanthus amarus protects against spatial memory impairment induced by lipopolysaccharide in mice
    Alagan A, Jantan I, Kumolosasi E, Azmi N
    Bioinformation, 2019;15(8):535-541.
    PMID: 31719762 DOI: 10.6026/97320630015535
    Phyllanthus amarus Schumach. and Thonn. is a wide spread medicinal herb with various traditional uses. It is well documented for its antioxidant, anti-inflammatory, and hepatoprotective activities. Therefore, it is of interest to evaluate the 80% ethanol extract of Phyllanthus amarus (PA) on spatial memory using the 8-radial arm maze (8-RAM) in mice after induction of neuro inflammation by lipopolysaccharide (LPS) in a 14- and 28-days treatment study. LC-MS/MS was performed to profile the chemical composition in PA extract. Mice were treated orally with 5% v/v tween 20, PA extract (100, 200 and 400 mg/kg), or ibuprofen (IBF 40 mg/kg) for 14 and 28 days. All groups were challenged with LPS (1 mg/kg) via intraperitoneal (i.p.) injection a day prior to the 8-RAM task except for the negative control group which received an i.p. injection of saline. Data obtained were analyzed with one-way ANOVA followed by post hoc Dunnett's test (comparison of all groups against vehicle control). Analysis of LC-MS/MS data revealed the presence of 16 compounds in the PA extract. Administration of PA extract at 200 and 400 mg/kg for 14 and 28 days significantly (*P<0.05) decreased the working and reference memory errors against LPS-induced spatial memory impairment. The observed protective action is possibly due to the putative antineuroinflammatory effects of PA. In conclusion, PA extract possess neuroprotective effects against spatial memory impairment mediated by LPS.
    Matched MeSH terms: Spatial Memory
  9. Tualang honey consumption enhanced hippocampal pyramidal count and spatial memory performance of adult male rats
    Mohd Amiruddin Kamarulzaidi, Zulkifli Mohd. Yusoff MY, Abdul Majid Mohamed, Durriyyah Sharifah Hasan Adli
    Sains Malaysiana, 2016;45:215-220.
    As a natural anti-oxidant source, Tualang honey, produced by wild bees nesting on the Tualang tree (Koompassia excelsa) is expected to have positive influence on health, including memory. This study investigated the effect of Tualang honey on the cell count of memory formation related hippocampal pyramidal neuron and on spatial memory performance (SMP) of rats using the radial arm maze (RAM). Sprague Dawley male rats (n=24), 7-8 weeks old were divided into two groups; experimental group group force-fed 1 mL/100 g body weight with 70% honey (HG); and the control group with 0.9% saline (CG) for 12 weeks. Nissl staining technique (with cresyl violet) was employed for neurohistological analysis of the hippocampal tissue. Six randomly selected rats from each group were used for the neuronal soma counting of pyramidal cell layer CA1, CA3a and CA3c regions. Two-way ANOVA analysis showed positively significant differences between treatment and control groups for SMP comparison of working memory and reference memory components, as well as the number of pyramidal neurons. Hence, this positive effects of Tualang honey, as demonstrated behaviorally and neurohistologically, supported report that Tualang honey could improve memory and deter hippocampal morphological impairments; possibly due to its high anti-oxidant properties.
    Matched MeSH terms: Spatial Memory
  10. Fulltext Stingless Bee Honey Improves Spatial Memory in Mice, Probably Associated with Brain-Derived Neurotrophic Factor (BDNF) and Inositol 1,4,5-Triphosphate Receptor Type 1 (Itpr1) Genes
    Mustafa MZ, Zulkifli FN, Fernandez I, Mariatulqabtiah AR, Sangu M, Nor Azfa J, et al.
    Evid Based Complement Alternat Med, 2019;2019:8258307.
    PMID: 31885664 DOI: 10.1155/2019/8258307
    This study was conducted to evaluate the effects of stingless bee honey (SBH) supplementation on memory and learning in mice. Despite many studies that show the benefits of honey on memory, reports on the nootropic effects of SBH are still lacking, and their underlying mechanism is still unclear. SBH is a honey produced by the bees in the tribe of Meliponini that exist in tropical countries. It features unique storage of honey collected in cerumen pots made of propolis. This SBH may offer a better prospect for therapeutic performance as the previous report identifies the presence of antioxidants that were greater than other honey produced by Apis sp. In this study, SBH was tested on Swiss albino mice following acute (7 days) and semichronic (35 days) supplementation. Experiments were then conducted using Morris water maze (MWM) behaviour analysis, RT-PCR for gene expression of mice striatum, and NMR for metabolomics analysis of the honey. Results indicate spatial working memory and spatial reference memory of mice were significantly improved in the honey-treated group compared with the control group. Improved memory consolidations were also observed in prolonged supplementation. Gene expression analyses of acutely treated mice demonstrated significant upregulation of BDNF and Itpr1 genes that involve in synaptic function. NMR analysis also identified phenylalanine, an essential precursor for tyrosine that plays a role at the BDNF receptor. In conclusion, SBH supplementation for seven days at 2000 mg/kg, which is equivalent to a human dose of 162 mg/kg, showed strong capabilities to improve spatial working memory. And prolonged intake up to 35 days increased spatial reference memory in the mice model. The phenylalanine in SBH may have triggered the upregulation of BDNF genes in honey-treated mice and improved their spatial memory performance.
    Matched MeSH terms: Spatial Memory
  11. Fulltext Nigella sativa Oil Enhances the Spatial Working Memory Performance of Rats on a Radial Arm Maze
    Sahak MK, Mohamed AM, Hashim NH, Hasan Adli DS
    Evid Based Complement Alternat Med, 2013;2013:180598.
    PMID: 24454487 DOI: 10.1155/2013/180598
    Nigella sativa, an established historical and religion-based remedy for a wide range of health problems, is a herbal medicine known to have antioxidant and neuroprotective effects. This present study investigated the effect of Nigella sativa oil (NSO) administration on the spatial memory performance (SMP) of male adult rats using eight-arm radial arm maze (RAM). Twelve Sprague Dawley rats (7-9 weeks old) were force-fed daily with 6.0  μ L/100 g body weight of Nigella sativa oil (NSO group; n = 6) or 0.1 mL/100 g body weight of corn oil (control) (CO group; n = 6) for a period of 20 consecutive weeks. For each weekly evaluation of SMP, one day food-deprived rats were tested by allowing each of them 3 minutes to explore the RAM for food as their rewards. Similar to the control group, the SMP of the treated group was not hindered, as indicated by the establishment of the reference and working memory components of the spatial memory. The results demonstrated that lesser mean numbers of error were observed for the NSO-treated group in both parameters as compared to the CO-treated group. NSO could therefore enhance the learning and memory abilities of the rats; there was a significant decrease in the overall mean number of working memory error (WME) in the NSO-treated group.
    Matched MeSH terms: Spatial Memory
  12. Fulltext Embelin Improves the Spatial Memory and Hippocampal Long-Term Potentiation in a Rat Model of Chronic Cerebral Hypoperfusion
    Bhuvanendran S, Bakar SNS, Kumari Y, Othman I, Shaikh MF, Hassan Z
    Sci Rep, 2019 10 10;9(1):14507.
    PMID: 31601902 DOI: 10.1038/s41598-019-50954-y
    Alzheimer's disease (AD) is the second most occurring neurological disorder after stroke and is associated with cerebral hypoperfusion, possibly contributing to cognitive impairment. In the present study, neuroprotective and anti-AD effects of embelin were evaluated in chronic cerebral hypoperfusion (CCH) rat model using permanent bilateral common carotid artery occlusion (BCCAO) method. Rats were administered with embelin at doses of 0.3, 0.6 or 1.2 mg/kg (i.p) on day 14 post-surgery and tested in Morris water maze (MWM) followed by electrophysiological recordings to access cognitive abilities and synaptic plasticity. The hippocampal brain regions were extracted for gene expression and neurotransmitters analysis. Treatment with embelin at the doses of 0.3 and 0.6 mg/kg significantly reversed the spatial memory impairment induced by CCH in rats. Embelin treatment has significantly protected synaptic plasticity impairment as assessed by hippocampal long-term potentiation (LTP) test. The mechanism of this study demonstrated that embelin treatment alleviated the decreased expression of BDNF, CREB1, APP, Mapt, SOD1 and NFκB mRNA levels caused by CCH rats. Furthermore, treatment with embelin demonstrated neuromodulatory activity by its ability to restore hippocampal neurotransmitters. Overall these data suggest that embelin improve memory and synaptic plasticity impairment in CCH rats and can be a potential drug candidate for neurodegenerative disease-related cognitive disorders.
    Matched MeSH terms: Spatial Memory/drug effects
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