Quantitative Measurement of Changes in Amyloid-β(40) in the Rat Brain and Cerebrospinal Fluid following Treatment with the γ-Secretase Inhibitor LY-411575 [N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide]
| Autor: | Christine Pattison, John R. Atack, Semantha Ellis, Franklin Otu, Alan Nadin, Huw D. Lewis, Mark T. Jay, Jerome Ma, Jonathan D. Best, Timothy Harrison, Toni Williamson, Michael Reilly, Mark S. Shearman |
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| Rok vydání: | 2005 |
| Předmět: |
Pharmacology
chemistry.chemical_classification Genetically modified mouse medicine.medical_specialty biology business.industry Central nervous system Peptide Molecular biology Dose–response relationship Cerebrospinal fluid Endocrinology medicine.anatomical_structure chemistry In vivo Internal medicine medicine biology.protein Amyloid precursor protein Molecular Medicine business Amyloid precursor protein secretase |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 313:902-908 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.104.081174 |
| Popis: | The efficacy of gamma-secretase inhibitors in vivo has, to date, been generally assessed in transgenic mouse models expressing increased levels of amyloid-beta (Abeta) peptide thereby allowing the detection of changes in Abeta production. However, it is not clear whether the in vivo potency of gamma-secretase inhibitors is independent of the level of amyloid precursor protein expression. In other words, does a gamma-secretase inhibitor have the same effect in nontransgenic physiological animals versus transgenic overexpressing animals? In the present study, an immunoassay has been developed which can detect Abeta(40) in the rat brain, where concentrations are much lower than those seen in transgenic mice such as Tg2576 (c. 0.7 and 25 nM, respectively) and in cerebrospinal fluid (CSF, c. 0.3 nM). Using this immunoassay, the effects of the gamma-secretase inhibitor LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide] were assessed and robust dose-dependent reductions in rat brain and CSF Abeta(40) levels were observed with ID(50) values of 1.3 mg/kg for both brain and CSF. These values were comparable with those calculated for LY-411575 in transgenic mice. Time course experiments using LY-411575 demonstrated comparable temporal reductions in rat brain and CSF Abeta(40), further suggesting these two pools of Abeta are related. Accordingly, when all the data for the dose-response curve and time course were correlated, a strong association was observed between the brain and CSF Abeta(40) levels. These data demonstrate the utility of the rat as a novel approach for assessing the effects of gamma-secretase inhibitors on central nervous system Abeta(40) levels in vivo. |
| Databáze: | OpenAIRE |
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