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Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice.

Abstract

BACKGROUND

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Abeta42 in cell culture and animal models, and that the effect of NSAIDs on Abeta42 is independent of the inhibition of cyclooxygenase by these compounds. Since Abeta42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Abeta42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Abeta42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Abeta loads in Tg2576 APP mice.

RESULTS

A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Abeta pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Abeta was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Abeta plaque burden but no significant improvement in spatial learning.

CONCLUSION

We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Abeta42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of R-flurbiprofen as an AD therapeutic and its possible mechanisms of action.

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  • Authors+Show Affiliations

    ,

    Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. kukar.thomas@mayo.edu <kukar.thomas@mayo.edu>

    , , , , , ,

    Source

    BMC neuroscience 8: 2007 Jul 24 pg 54

    MeSH

    Alzheimer Disease
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Animals
    Brain
    Cyclooxygenase Inhibitors
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Drug Administration Schedule
    Encephalitis
    Female
    Flurbiprofen
    Learning Disorders
    Maze Learning
    Memory Disorders
    Mice
    Mice, Transgenic
    Peptide Fragments
    Plaque, Amyloid
    Stereoisomerism
    Treatment Outcome

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    17650315

    Citation

    Kukar, Thomas, et al. "Chronic Administration of R-flurbiprofen Attenuates Learning Impairments in Transgenic Amyloid Precursor Protein Mice." BMC Neuroscience, vol. 8, 2007, p. 54.
    Kukar T, Prescott S, Eriksen JL, et al. Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007;8:54.
    Kukar, T., Prescott, S., Eriksen, J. L., Holloway, V., Murphy, M. P., Koo, E. H., ... Nicolle, M. M. (2007). Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neuroscience, 8, p. 54.
    Kukar T, et al. Chronic Administration of R-flurbiprofen Attenuates Learning Impairments in Transgenic Amyloid Precursor Protein Mice. BMC Neurosci. 2007 Jul 24;8:54. PubMed PMID: 17650315.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. AU - Kukar,Thomas, AU - Prescott,Sonya, AU - Eriksen,Jason L, AU - Holloway,Vallie, AU - Murphy,M Paul, AU - Koo,Edward H, AU - Golde,Todd E, AU - Nicolle,Michelle M, Y1 - 2007/07/24/ PY - 2006/11/29/received PY - 2007/07/24/accepted PY - 2007/7/26/pubmed PY - 2007/10/3/medline PY - 2007/7/26/entrez SP - 54 EP - 54 JF - BMC neuroscience JO - BMC Neurosci VL - 8 N2 - BACKGROUND: Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Abeta42 in cell culture and animal models, and that the effect of NSAIDs on Abeta42 is independent of the inhibition of cyclooxygenase by these compounds. Since Abeta42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Abeta42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Abeta42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Abeta loads in Tg2576 APP mice. RESULTS: A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Abeta pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Abeta was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Abeta plaque burden but no significant improvement in spatial learning. CONCLUSION: We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Abeta42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of R-flurbiprofen as an AD therapeutic and its possible mechanisms of action. SN - 1471-2202 UR - https://www.unboundmedicine.com/medline/citation/17650315/Chronic_administration_of_R_flurbiprofen_attenuates_learning_impairments_in_transgenic_amyloid_precursor_protein_mice_ L2 - https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-8-54 DB - PRIME DP - Unbound Medicine ER -