Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139
| Autor: | Douglas K. Spracklin, Karl E.G. Richter, Barbara Tate, Michael J. Karmilowicz, Tracy M. Brown, Lit-Fui Lau, Mary A. Piotrowski, David D. Auperin, Ping Du, Thomas A. Lanz, Nikolay Pozdnyakov, Charles E. Nolan, Charles F. Ebbinghaus, Kathleen M. Wood, James E. Finley, Kieran F. Geoghegan, Joel B. Schachter, Qing Fei, Yuhpyng L. Chen |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty Time Factors Mutant Guinea Pigs Guinea pig Mice Cerebrospinal fluid In vivo Internal medicine medicine Animals Enzyme Inhibitors Cells Cultured Pharmacology Alanine Amyloid beta-Peptides Dose-Response Relationship Drug Chemistry Azepines Embryonic stem cell In vitro Endocrinology Cell culture Molecular Medicine Amyloid Precursor Protein Secretases Semagacestat medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 319(2) |
| ISSN: | 0022-3565 |
| Popis: | LY-450139 is a gamma-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-beta (Abeta) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate Abeta responses to LY-450139 in the guinea pig, a nontransgenic model that has an Abeta sequence identical to that of human. Male guinea pigs were treated with LY-450139 (0.2-60 mg/kg), and brain, cerebrospinal fluid, and plasma Abeta levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma Abeta levels at early time points, with return to baseline within hours. Higher doses inhibited Abeta levels in all compartments at early time points, but elevated plasma Abeta levels at later time points. To determine whether this phenomenon occurs under steady-state drug exposure, guinea pigs were implanted with subcutaneous minipumps delivering LY-450139 (0.3-30 mg/kg/day) for 5 days. Plasma Abeta was significantly inhibited at 10-30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of Abeta elevation by LY-450139, H4 cells overexpressing the Swedish mutant of amyloid-precursor protein and a mouse embryonic stem cell-derived neuronal cell line were studied. In both cellular models, elevated levels of secreted Abeta were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the gamma-secretase complex, eliciting Abeta lowering at high concentrations but Abeta elevation at low concentrations. |
| Databáze: | OpenAIRE |
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