Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in <scp>APP</scp>swe/<scp>PS</scp>1dE9 Transgenic Mice

Shi, Jian-Quan; Wang, Bian-Rong; Tian, You‐Yong; Xu, Jun; Li, Gao; Zhao, Shuli; Jiang, Teng; Xie, Hong‐Guang

doi:10.1111/cns.12144

Cited by 101 publications

(97 citation statements)

References 60 publications

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“…Aβ clearance is at least partially dependent on activity of astrocytes and microglia. Plaques are often surrounded by microglia, which may explain why HFD-fed animals exhibit a heavier microglial burden than WT or LFD mice (Ramos-Rodriguez, et al, 2014, Shi, et al, 2013). The reversible effect of HFD on both GFAP and TNF-α, supports the hypothesis that glial cells play an important role in the changes in Aβ level reported here.…”

Section: Discussionmentioning

confidence: 99%

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Walker

Dixit

Saulsberry

et al. 2017

Neurobiology of Disease

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This study assessed the extent to which high fat diet (HFD)-induced β-amyloid accumulation and cognitive decline in APP/PSEN1 mice are reversible through control of fat intake. Ten months of HFD (60% calories from fat) led to significant deficits in a 2-trial Y maze task, and nest building assay, and decreased voluntary locomotor activity. The HFD induced an inflammatory response, indicated by increased expression of several inflammatory markers. Substituting a low fat diet led to pronounced weight loss and correction of glucose intolerance, decreases in the inflammatory response, and improved performance on behavioral tasks in both wild-type and APP/PSEN1 transgenic mice. Insoluble β-amyloid levels, and extent of tau phosphorylation were also lower following dietary reversal in APP/PSEN1 mice compared to high fat-fed animals, indicating that the inflammatory response may have contributed to key pathogenic pathways in the Alzheimer’s disease model. The data suggest that weight loss can be a vital strategy for cognitive protection, but also highlight potential mechanisms for intervention when sustained weight loss is not possible.

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Section: Discussionmentioning

confidence: 99%

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Walker

Dixit

Saulsberry

et al. 2017

Neurobiology of Disease

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“…Among several antiepileptic drugs tested, only levetiracetam reduced epileptiform activity and reversed cognitive deficits in human APP transgenic mice [85,86]. Levetiracetam is currently undergoing a Phase IIa clinical trial for subclinical epileptiform activity and/or improved cognition in patients with AD (ClinicalTrials.gov identifier: NCT02002819).…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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“…Specifically, low dose administration of the atypical antiepileptic, levetiracetam (LEV) improves performance of aged rats with memory impairment in hippocampal-dependent tasks (Koh et al, 2010) and reduces firing rates of overactive hippocampal neurons (Robitsek et al, 2015). Therapeutic efficacy with this treatment has also been demonstrated on both behavior and hippocampal physiology in AD models of amyloid overexpression (Devi and Ohno, 2013; Hall et al, 2015; Sanchez et al, 2012; Shi et al, 2013; Suberbielle et al, 2013). Clinical studies in patients diagnosed with aMCI similarly show reductions in task-related fMRI hippocampal activation in a low dose range that concomitantly improves performance on a behavioral task that targets specific hippocampal-dependent computational functions critical for episodic memory (Bakker et al, 2012; 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Treatments to reduce hyperactivity not only improve performance on memory tasks in aged rats (Koh et al, 2010; 2013), but also have efficacy in transgenic AD mouse models (Sanchez et al, 2012; Shi et al, 2013) and in human clinical studies of patients with aMCI (Bakker et al, 2012; 2015). Specifically, low dose administration of the atypical antiepileptic, levetiracetam (LEV) improves performance of aged rats with memory impairment in hippocampal-dependent tasks (Koh et al, 2010) and reduces firing rates of overactive hippocampal neurons (Robitsek et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Heightened cortical excitability in aged rodents with memory impairment

Haberman

Koh

Gallagher

2017

Neurobiology of Aging

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Elevated excitability in the hippocampus has emerged as a key contributor to reduced memory function in aging and in cognitive impairment prodromal to Alzheimer’s disease. Here, we investigated the relationship between neural activity and memory in the hippocampus and a connectional cortical network using an aged rat model of individual differences for memory impairment. The expression of cFos was used as a measure of pharmacologically induced neural activity. Aged memory-impaired rats exhibited elevated cFos relative to young adult and aged unimpaired rats in the CA3 subfield of the hippocampus and in several cortical regions including the retrosplenial, parietal, and orbitofrontal cortices. Strong correlations between cFos intensity and task performance across the activated network showed a tight coupling between excitability and cognitive phenotype in aging. Elevated neural excitability extending beyond the hippocampus to interconnected posterior cortex (retrosplenial/parietal) was reduced by treatment with levetiracetam, a therapeutic with behavioral efficacy that has previously translated from rodent models of age-related impairment and Alzheimer’s disease to humans with amnestic mild cognitive impairment.

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Antiepileptics Topiramate and Levetiracetam Alleviate Behavioral Deficits and Reduce Neuropathology in APPswe/PS1dE9 Transgenic Mice

Abstract: Therefore, TPM and LEV might have the potential to treat AD effectively in patient care.

Cited by 101 publications

References 60 publications

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Heightened cortical excitability in aged rodents with memory impairment

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