1. Determination of guinea-pig cortical γ-secretase activity ex vivo following the systemic administration of a γ-secretase inhibitor
- Author
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Joanne E. Hogg, T. Townend, A.M. Lad, Peter H. Hutson, V. Lee, Fraser Murray, Sarah Grimwood, Dirk Beher, Mark S. Shearman, M. Vithlani, James Peachey, and M T Jay
- Subjects
Male ,Amyloid ,Guinea Pigs ,Administration, Oral ,Pharmacology ,Arsenicals ,law.invention ,Guinea pig ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,law ,In vivo ,Endopeptidases ,Animals ,Aspartic Acid Endopeptidases ,Protease Inhibitors ,Cerebral Cortex ,chemistry.chemical_classification ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Propanamide ,Peptide Fragments ,Enzyme Activation ,Enzyme ,chemistry ,Bisbenzimidazole ,Recombinant DNA ,Systemic administration ,Amyloid Precursor Protein Secretases ,Ex vivo - 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 gamma-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 gamma-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 gamma-secretase inhibitor reduces amyloid beta-peptide, but also the inhibition of brain gamma-secretase activity, as a more direct estimate of enzyme occupancy.
- Published
- 2005
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