DAPT

γ secretase(Aβ)；Aβ；Aβ42

432.46

DMSO ：43.2 mg/mL (100 mM)

白色至类白色固体

DAPT presents the dose-dependent inhibition upon both total Ab and Ab42 production in human primary neuronal cultures. Both measures of Ab production are similarly inhibited with potencies (Ab total IC50: 115 nM, Ab42 IC50: 200 nM) of 5±10-fold lower than is observed in HEK 293 cells. Although the application of the maximum dose of DAPT at 75 μM had no obvious effect on cell survival, it substantially retarded CNE-2 cell proliferation in a dose-dependent manner. CNE-2 cells were treated with increasing concentrations of DAPT, and the γ-secretase-generated Notch 1 fragment Val1744-NICD was decreased after 48 h in a dose-dependent manner (P<0.01). The activation of γ-secretase was almost completely inhibited by DAPT at the concentration of 50 μM .

DAPT was administered to PDAPP mice (100 mg/kg s.c.) and the levels of DAPT and Ab were examined in the brain cortex. Peak DAPT levels of 490 ng/g were achieved in the brain 3 h after treatment and level greater than 100 ng/g (~200 nM) were sustained throughout the first 18 h. These brain concentrations of DAPT are in excess of its IC50 for lowering Ab in neuronal cultures (115 nM) and resulted in a robust and sustained pharmacodynamic effect in vivo. DAPT could reduce the brain water content of ipsilateral hemispheres. In the sham-operated group, water content was 78.83 ± 0.35%. In DAPT group, brain water content was reduced compared with MCAO group (80.89 ± 0.51 vs. 83.84 ± 0.75%, P\0.05). These data indicated that DAPT protected the brain against brain ischemia damage at the early stage of cerebral ischemia.

GSI-IX；GSI IX；LY-374973

C₂₃H₂₆F2N₂O₄

208255-80-5