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Cyclosporins to treat alzheimer's disease

A technology for Alzheimer's disease and cyclosporine, applied in the direction of cyclosporine, cyclic peptide components, nervous system diseases, etc., can solve the problem of insufficient immunosuppressive activity

Inactive Publication Date: 2007-06-20
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although immunophilin binding is required, its immunosuppressive activity is insufficient for these drugs

Method used

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  • Cyclosporins to treat alzheimer's disease
  • Cyclosporins to treat alzheimer's disease
  • Cyclosporins to treat alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] Presenilin Processing: Overexpression of cDNA was observed to increase Aβ levels of C99 substrates, suggesting increased GACE-mediated APP cleavage. Since CPZ and CyD significantly enhanced the processing of C99 and increased Aβ42 secretion, they were selected for further study. PS1 N-terminal fragment (NTF) levels in HEK293 cells transfected with CPZ or CyD were detected. In cells stably transfected with PS1, full-length PS1 and NTF can be readily detected. In contrast, endogenous full-length PS1 and NTF levels were lower in untransfected HEK cells. Significant increases in PS1 NTF levels in cells overexpressing CPZ or CyD indicated that these fragments were produced at a higher rate or that endogenous NTFs were stabilized during the 48 hours of transfection.

[0125] CPZ Analysis: CPZ is a member of the carboxypeptidase (CP) gene family, belonging to the CPE subfamily, known to process bioactive neuropeptides (Song and Fricker 1997). CPE-associated enzymes are ofte...

Embodiment 2

[0136] C99 and Notch cleavage

[0137] HEK 293 stable cell lines were generated using modified C99 or Notch transmembrane sequences with signal peptide, TGN retention sequence, and insertion of the GAL4-NLS-VP16 sequence at Q56 / Y57 as described by Maltrese, Wilson et al. 2001 . The cells also stably expressed the 5xGAL4RE-luciferase reporter gene constructs (RD-2002-01437 and RD-2001-02419). GACE activity in these cells was measured when the C99 transgene was cleaved, thereby activating the Gal4 luciferase reporter gene. These HEK stable cells were treated with cyclosporin A, Sangliferhin A, FK506, or N-methyl-4-valine-cyclosporine and the IC for C99 cleavage was determined 50 . GALVP alone can be used as a negative control. GALVP IC for cyclosporin A, N-methyl-4-valine-cyclosporine, Sangliferhin A and FK506 50 6.9, 9.9, >20, and >20 μM, respectively, suggesting a clear link between inhibition of C99 cleavage and cell viability as these compounds were not toxic until >40 ...

Embodiment 3

[0139] Caspase-3 activation

[0140] Recent studies suggest that activation of caspase-3 can lead to increased Aβ secretion and stabilization of proteins in the GACE complex (Tesco, Koh et al. 2003). Since both CyD and CPZ enhance Aβ secretion and stabilize PS1 NTF, the level of caspase-3 activation was analyzed in CyD and CPZ overexpressing cells. HEK 293 cells were transiently transfected with CyD and CPZ together with APPwt for 24 hours, saponin permeabilized, fixed and probed with FITC-conjugated monoclonal antibody against active caspase-3. Negative control cells were transfected with empty vector and APPwt, while positive control cells were treated with 1 μM staurosporine for 6 hr before analysis. In cells expressing CyD, 52% of the cells tested were positive for active caspase-3, whereas in cells expressing CPZ, 48% of cells were positive for caspase-3. These results indicate that overexpression of these proteins induces the activation of caspase-3, suggesting this as...

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Abstract

Non-immunosuppressive, cyclophilin-binding cyclosporins, are useful as neuroprotective agents, e.g. in the prevention or treatment of pathological conditions associated with A beta secretion and / or production.

Description

technical field [0001] The present invention relates to a new application of cyclosporine, especially a new pharmaceutical application of non-immunosuppressive cyclophilin binding cyclosporine. Background technique [0002] Cyclosporin A (CsA) binds to immunophilins such as cyclophilin (CyP), while FK506 and rapamycin, both immunophilin binding compounds, bind to FK506 binding protein (FKBP). Although immunophilin binding is required, it is not sufficient for the immunosuppressive activity of these drugs. Biological effects are observed when the drug / immunophilin complex interacts with a third effector protein. For example, the CyP-CsA and FKBP-FK506 complexes inhibit the serine / threonine phosphatase activity of calcineurin, thereby blocking the production of cytokines such as interleukin-2,4. On the other hand, the FKBP-rapamycin complex inhibits a kinase called FRAP (also known as RAFT or mTOR) 5, which is involved in interleukin-2 receptor-mediated T cell proliferation....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/13C07K7/64A61P25/00A61P25/28A61P25/16
CPCA61K38/13C07K7/645A61P25/00A61P25/14A61P25/16A61P25/28A61P43/00
Inventor D·科恩L·A·该赛
Owner NOVARTIS AG
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