Determination of guinea-pig cortical γ-secretase activity ex vivo following the systemic administration of a γ-secretase inhibitor

S. Grimwood, J. Hogg, M. T. Jay, A. M. Lad, V. Lee, F. Murray, J. Peachey, T. Townend, M. Vithlani, D. Beher, M. S. Shearman, P. H. Hutson

    Research output: Contribution to journalArticlepeer-review

    Abstract

    (2S)-2-{[(3,5-Diflurophenyl)acetyl]amino}-N-[(3S)-1-methyl-2-oxo-5-phenyl- 2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanamide (compound E) is a γ-secretase inhibitor capable of reducing amyloid beta-peptide (1-40) and amyloid beta-peptide (1-42) levels. In this study we investigated the effect of in vivo administration of compound E on guinea-pig plasma, CSF and cortical amyloid beta-peptide (1-40) concentration. Using repeated sampling of CSF, compound E (30 mg/kg p.o.) was shown to cause a time-dependent decrease in CSF amyloid beta-peptide (1-40) levels, which was maximal at 3 h (70% inhibition), compared to baseline controls. After 3 h administration, compound E (3, 10 and 30 mg/kg p.o.), reduced plasma, CSF and DEA-extracted cortical amyloid beta-peptide (1-40) levels by 95, 97 and 99%; 26, 48 and 78%; 32, 33, and 47%, respectively, compared to vehicle control values. In the same animals, compound E (3, 10 and 30 mg/kg p.o.) inhibited cortical γ-secretase activity, determined ex vivo using the recombinant substrate C100Flag, by 40, 71 and 79% of controls, respectively. These data demonstrate the value of determining not only the extent by which systemic administration of a γ-secretase inhibitor reduces amyloid beta-peptide, but also the inhibition of brain γ-secretase activity, as a more direct estimate of enzyme occupancy. © 2005 Elsevier Ltd. All rights reserved.
    Original languageEnglish
    Pages (from-to)1002-1011
    Number of pages9
    JournalNeuropharmacology
    Volume48
    Issue number7
    DOIs
    Publication statusPublished - Jun 2005

    Keywords

    • γ-Secretase
    • Amyloid beta-peptide
    • Ex vivo enzyme activity assay
    • Guinea-pig
    • In vivo enzyme activity assay

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