DAPT

DAPT (GSI-IX) is a potent and orally active γ-secretase inhibitor with IC₅₀s of 115 nM and 200 nM for total amyloid-β (Aβ) and Aβ₄₂, respectively. DAPT inhibits the activation of Notch 1 signaling and induces cell differentiation. DAPT also induces autophagy and apoptosis. DAPT has neuroprotection activity and has the potential for autoimmune and lymphoproliferative diseases, degenerative disease and cancers treatment^[1][2]. IC50 & Target:IC50: 115 nM (Aβ), 200 nM (Aβ42)^[5] In Vitro:DAPT inhibits Aβ production over 90%, effects only a modest reduction in APPβ in the culture media. Although APPβ is reduced by about 30% by DAPT treatment, this effect is not concentration-dependent and is reversed by the removal of DAPT^[1].
CNE-2 cells are treated with increasing concentrations of DAPT (0, 25, 50 and 75 μM), and the γ-secretase-generated Notch 1 fragment Val1744-NICD is decreased after 48 h in a dose-dependent manner (P<0.01). The activation of γ-secretase is almost completely inhibited by DAPT at the concentration of 50 μM^[3]. In Vivo:DAPT is administered to PDAPP mice (100 mg/kg s.c.) and the levels of DAPT and Aβ are examined in the brain cortex. Peak DAPT levels of 490 ng/g are achieved in the brain 3 h after treatment, and levels greater than 100 ng/g (~200 nM) are sustained throughout the first 18 h. These brain concentrations of DAPT are in excess of its IC₅₀ for lowering Aβ in neuronal cultures (115 nM), and results in a robust and sustains pharmacodynamic effect^[1].
DAPT protects brain against cerebral ischemia by down-regulating the expression of Notch 1 and Nuclear factor kappa B in rats. Western blot analyses also show a significant decrease of Notch 1 and NF-κB expression in DAPT (0.03 mg/kg) group (P<0.05 vs. MCAO group)^[2].