The Novel γ Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) Reduces Amyloid Plaque Deposition without Evidence of Notch-Related Pathology in the Tg2576 Mouse
| العنوان: | The Novel γ Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) Reduces Amyloid Plaque Deposition without Evidence of Notch-Related Pathology in the Tg2576 Mouse |
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| المؤلفون: | David Smith, John R. Atack, Ruth O'Donnell, Jonathan D. Best, Mark S. Shearman, Semantha Ellis, Michael Reilly, Philippe A. Laroque, Ian Churcher, Tim Harrison, Huw D. Lewis, Christine Boussiquet-Leroux, Thomas W. Rosahl, Neil Wilkie |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 320:552-558 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Pharmacology, chemistry.chemical_classification, Pathology, medicine.medical_specialty, biology, P3 peptide, Spleen, Cortex (botany), medicine.anatomical_structure, Enzyme, Notch Family, chemistry, In vivo, mental disorders, medicine, Amyloid precursor protein, biology.protein, Molecular Medicine, Receptor |
| الوصف: | There is a substantial body of evidence indicating that beta-amyloid peptides (Abeta) are critical factors in the onset and development of Alzheimer's disease (AD). One strategy for combating AD is to reduce or eliminate the production of Abeta through inhibition of the gamma-secretase enzyme, which cleaves Abeta from the amyloid precursor protein (APP). We demonstrate here that chronic treatment for 3 months with 3 mg/kg of the potent, orally bioavailable and brain-penetrant gamma-secretase inhibitor N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) attenuates the appearance of amyloid plaques in the Tg2576 mouse. These reductions in plaques were also accompanied by a decrease in the level of reactive gliosis. The morphometric and histological measures agreed with biochemical analysis of Abeta(40) and Abeta(42) in the cortex. Interestingly, the volume of the plaques across treatment groups did not change, indicating that reducing Abeta levels does not significantly alter deposit growth once initiated. Furthermore, we demonstrate that these beneficial effects can be achieved without causing histopathological changes in the ileum, spleen, or thymus as a consequence of blockade of the processing of alternative substrates, such as the Notch family of receptors. This indicates that in vivo a therapeutic window between these substrates seems possible--a key concern in the development of this approach to AD. An understanding of the mechanisms whereby MRK-560 shows differentiation between the APP and Notch proteolytic pathway of gamma-secretase should provide the basis for the next generation of gamma-secretase inhibitors. |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::bdf996bb8604da3731d4b9597483caacTest https://doi.org/10.1124/jpet.106.114330Test |
| رقم الانضمام: | edsair.doi...........bdf996bb8604da3731d4b9597483caac |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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