DAPT (GSI-IX)
DAPT (GSI-IX) is a novel γ-secretase inhibitor, which inhibits Aβ production with IC50 of 20 nM in HEK 293 cells. DAPT enhances the apoptosis of human tongue carcinoma cells and regulates autophagy.
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Neuroscience,2012 May 17;210:99-109.
The γ-secretase blocker DAPT impairs recovery from lipopolysaccharide-induced inflammation in rat brain.[Pubmed:
22445932]
γ-Secretase is an important contributing enzyme in Alzheimer's disease and is therefore an important therapeutic target. However, the impact of γ-secretase inhibition is not well studied in acute neuroinflammation induced by systemic infection.
METHODS AND RESULTS:
In this study the influence of γ-secretase on the expression of some proinflammatory markers was assessed in the acute phase as well as the subsiding phase of neuroinflammation. Cerebral γ-secretase cleavage activity was measured by a fluorometric assay after lipopolysaccharide (LPS) intraperitoneal administration. Time profiles of TNF-α and COX-II expression were then determined to detect the time points relevant to the maximal inflammatory responses and the subsequent recovery phase. γ-Secretase activity coincident with TNF-α protein expression returned to its basal level till 8-12 h after systemic challenge with low dose LPS while COX-II over expression lasted for 48-72 h later. Pharmacological inhibition of γ-secretase with local or systemic administration of DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester) was performed to indicate the results on the developmental and sinking phases of inflammatory responses in 6 and 72 h post LPS respectively. Our results demonstrate that both local and systemic modulation of γ-secretase hyper-activity with DAPT increase the duration of TNF-α, COX-II, and NFκB induction. We consistently found mild augmented apoptosis in animals treated with DAPT as determined by measuring cleaved caspase-3 expression and by TUNEL assay 72 h following LPS injection.
CONCLUSIONS:
These results suggest that γ-secretase modulation interferes with certain immune regulatory pathways which may restrict some inflammatory transcription factors such as NF-κB.
J Neurochem,2001 Jan;76(1):173-81.
Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.[Pubmed:
11145990]
Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease.
METHODS AND RESULTS:
We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h.
CONCLUSIONS:
These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.
APMIS,2012 Jun;120(6):441-50.
Down-regulation of Notch receptor signaling pathway induces caspase-dependent and caspase-independent apoptosis in lung squamous cell carcinoma cells.[Pubmed:
22583356]
Cell lines:SK-MES-1 cells
Concentrations: 2.5 μM to 160 μM
Incubation Time: 72 hours
Method:
Cells are seeded into 96-well plates and exposed to 0.1% DMSO or DAPT at concentrations in the range of 2.5 μM–160 μM for 72 hours. Cytotoxicity is determined with 3-(4, 5)-dimethylthiahiazo-(-z-y1)-3, 5-di-phenytetrazoliumromide (MTT) dye reduction assay with minor modifications. Briefly, after incubation with DAPT, 20 μL MTT solution (5 mg/mL in PBS) is added to 180 μL medium in each well and plates are incubated for 4 hours at 37 °C, and subsequently 150 μL DMSO is added to each well, and mixed by shaking at room temperature for 15 minutes. Absorption is measured by an enzyme-linked immunosorbent assay at 490 nm to determine absorbance values. α-MEM supplemented with the same amount of MTT solution and solvent is used as blank solution. The IC50 value is calculated using PROBIT program in SPSS.
J Neurochem, 2001 Jan;76(1):173-81.
Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.[Pubmed:
11145990]
Animal Models: Heterozygous PDAPP transgenic mice
overexpressing the APPV717F mutant form of the amyloid precursor protein.
Dosages: ≤100 mg/kg
Administration: Administered via p.o.
