ID1201, the ethanolic extract of the fruit of Melia toosendan ameliorates impairments in spatial learning and reduces levels of amyloid beta in 5XFAD mice

Cho, Woo-Hyun; Park, Jung-Cheol; Kim, Dong‐Hee; Kim, Minsu; Lee, Sun-Young; Park, Hanbyeol; Kang, Jae-Hoon; Yeon, Seung-Woo; Han, Jung‐Soo

doi:10.1016/j.neulet.2014.09.036

Cited by 13 publications

(10 citation statements)

References 22 publications

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“…In the present study, we demonstrate the neuroprotective effect of a long-term treatment with MpHE in the 5XFAD mouse model of AD. This model has been widely used to examine the therapeutic value of candidate agents for AD treatment [52–54], displaying age-dependent neurological and motor deficits that mimic common phenotypes seen in AD patients, without the presence of neurofibrillary tangles [55]. In addition, we also provide evidence indicating that the MpHE attenuates the negative effect of chronic peripheral inflammation on the development of AD pathological hallmarks.…”

Section: Discussionmentioning

confidence: 66%

Malva parviflora extract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer’s disease by restoring microglial function via a PPAR-γ-dependent mechanism

Medrano-Jiménez

Carrillo

Pedraza-Escalona

et al. 2019

J Neuroinflammation

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Background Alzheimer’s disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity exacerbates learning and memory deficits in humans and in animal models of AD. Consequently, the long-term use of non-steroidal anti-inflammatory agents diminishes the risk for developing AD, but the side effects produced by these drugs limit their prophylactic use. Thus, plants natural products have become an excellent option for modern therapeutics. Malva parviflora is a plant well known for its anti-inflammatory properties. Methods The present study was aimed to determine the anti-inflammatory potential of M . parviflora leaf hydroalcoholic extract (MpHE) on AD pathology in lean and obese transgenic 5XFAD mice, a model of familial AD. The inflammatory response and Amyloid β (Aβ) plaque load in lean and obese 5XFAD mice untreated or treated with MpHE was evaluated by immunolocalization (Iba-1 and GFAP) and RT-qPCR (TNF) assays and thioflavin-S staining, respectively. Spatial learning memory was assessed by the Morris Water Maze behavioral test. Microglia phagocytosis capacity was analyzed in vivo and by ex vivo and in vitro assays, and its activation by morphological changes (phalloidin staining) and expression of CD86, Mgl1, and TREM-2 by RT-qPCR. The mechanism triggered by the MpHE was characterized in microglia primary cultures and ex vivo assays by immunoblot (PPAR-γ) and RT-qPCR (CD36) and in vivo by flow cytometry, using GW9662 (PPAR-γ inhibitor) and pioglitazone (PPAR-γ agonist). The presence of bioactive compounds in the MpHE was determined by HPLC. Results MpHE efficiently reduced astrogliosis, the presence of insoluble Aβ peptides in the hippocampus and spatial learning impairments, of both, lean, and obese 5XFAD mice. This was accompanied by microglial cells accumulation around Aβ plaques in the cortex and the hippocampus and decreased expression of M1 inflammatory markers. Consistent with the fact that the MpHE rescued microglia phagocytic capacity via a PPAR-γ/CD36-dependent mechanism, the MpHE possess oleanolic acid and scopoletin as active phytochemicals. Conclusions M . parviflora suppresses neuroinflammation by inhibiting microglia pro-inflammatory M1 phenotype and promoting microglia phagocytosis. Therefore, M . parviflora phytochemicals represent an alternative to prevent cognitive impairment associated with a metabolic disorder as well as an effective prophylactic candidate for AD progression. Electronic supplementary material The online version of this article (10.1186/s12974-019-1515-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 66%

Malva parviflora extract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer’s disease by restoring microglial function via a PPAR-γ-dependent mechanism

Medrano-Jiménez

Carrillo

Pedraza-Escalona

et al. 2019

J Neuroinflammation

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“…Although all of the previous agents of this category failed in clinical trials, most of the new agents among them are studied in asymptomatic subjects at risk of developing AD [3,25]. Ongoing clinical trials with active or passive immunotherapy agents [26], with agents that reduce the Aβ plaque burden [27,28], with α-secretase modulators [29] or BACE inhibitors [25] are enrolling prodromal or mild AD patients to test the hypothesis of early pharmacological intervention [3,8].…”

Section: Inadequate Understanding Of the Complex Pathophysiology Of Amentioning

confidence: 99%

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

et al. 2019

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Despite all scientific efforts and many protracted and expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or have been abandoned in the last decade. The most probable explanations for failures of disease-modifying treatments (DMTs) for AD may include late initiation of treatments during the course of AD development, inappropriate drug dosages, erroneous selection of treatment targets, and mainly an inadequate understanding of the complex pathophysiology of AD, which may necessitate combination treatments rather than monotherapy. Clinical trials’ methodological issues have also been criticized. Drug-development research for AD is aimed to overcome these drawbacks. Preclinical and prodromal AD populations, as well as traditionally investigated populations representing all the clinical stages of AD, are included in recent trials. Systematic use of biomarkers in staging preclinical and prodromal AD and of a single primary outcome in trials of prodromal AD are regularly integrated. The application of amyloid, tau, and neurodegeneration biomarkers, including new biomarkers—such as Tau positron emission tomography, neurofilament light chain (blood and Cerebrospinal fluid (CSF) biomarker of axonal degeneration) and neurogranin (CSF biomarker of synaptic functioning)—to clinical trials allows more precise staging of AD. Additionally, use of Bayesian statistics, modifiable clinical trial designs, and clinical trial simulators enrich the trial methodology. Besides, combination therapy regimens are assessed in clinical trials. The above-mentioned diagnostic and statistical advances, which have been recently integrated in clinical trials, are relevant to the recent failures of studies of disease-modifying treatments. Their experiential rather than theoretical origins may better equip potentially successful drug-development strategies.

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“…Each mouse that participated in the behavioral task was sacrificed 7 days following the competition test [20,22]. Frontal cortices, hippocampal structures, and striatum were rapidly dissected and frozen at −70 • C until further processing.…”

Section: Brain Preparationmentioning

confidence: 99%

“…The brain structures were homogenized in cold lysis buffer (20 mM Tris/HCl, pH 7.5, 1.5 mM EDTA, 1% Triton X-100, 5% glycerol, 40 mM KCl, 1 mM Na 3 VO 4 , 1 mM PMSF, 0.5 mM DTT, and 1 mM NaF) [22]. After centrifugation at 14,000 rpm for 60 min at 4 • C, protein concentrations in the supernatants were measured using a bicinchoninic acid assay kit (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Immunoblot Analysesmentioning

confidence: 99%

4-Hydroxynonenal Immunoreactivity Is Increased in the Frontal Cortex of 5XFAD Transgenic Mice

et al. 2020

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Oxidative stress was implicated in the functional impairment of the frontal cortex observed in early Alzheimer’s disease (AD). To elucidate this role in an animal AD model, we assessed cognitive function of 4-month-old five familial AD (5XFAD) transgenic (Tg) mice using a learning strategy-switching task requiring recruitment of the frontal cortex and measuring levels of 4-hydroxy-2-trans-nonenal (4-HNE), a marker of oxidative stress, in their frontal cortex. Mice were sequentially trained in cued/response and place/spatial versions of the water maze task for four days each. 5XFAD and non-Tg mice exhibited equal performance in cued/response training. However, 5XFAD mice used spatial search strategy less than non-Tg mice in the spatial/place training. Immunoblot and immunofluorescence staining showed that 4-HNE levels increased in the frontal cortex, but not in the hippocampus and striatum, of 5XFAD mice compared to those in non-Tg mice. We report early cognitive deficits related to the frontal cortex and the frontal cortex’s oxidative damage in 4-month-old 5XFAD mice. These results suggest that 4-month-old 5XFAD mice be a useful animal model for the early diagnosis and management of AD.

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ID1201, the ethanolic extract of the fruit of Melia toosendan ameliorates impairments in spatial learning and reduces levels of amyloid beta in 5XFAD mice

Cited by 13 publications

References 22 publications

Malva parviflora extract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer’s disease by restoring microglial function via a PPAR-γ-dependent mechanism

Malva parviflora extract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer’s disease by restoring microglial function via a PPAR-γ-dependent mechanism

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

4-Hydroxynonenal Immunoreactivity Is Increased in the Frontal Cortex of 5XFAD Transgenic Mice

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