WO1998047518A1 - Verwendung von cholesterinsenkenden mitteln zur beeinflussing von signaltransduktionsvorgängen an der zellmembran, in die prophylaxe oder behandlung von prion-assorzierte- oder alzheimerische krankheit - Google Patents
Verwendung von cholesterinsenkenden mitteln zur beeinflussing von signaltransduktionsvorgängen an der zellmembran, in die prophylaxe oder behandlung von prion-assorzierte- oder alzheimerische krankheit Download PDFInfo
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- WO1998047518A1 WO1998047518A1 PCT/EP1998/002284 EP9802284W WO9847518A1 WO 1998047518 A1 WO1998047518 A1 WO 1998047518A1 EP 9802284 W EP9802284 W EP 9802284W WO 9847518 A1 WO9847518 A1 WO 9847518A1
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- cholesterol
- disease
- alzheimer
- signal transduction
- lowering agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- the present invention relates to the use of cholesterol-lowering agents for the prophylaxis or treatment of diseases which are associated with a change in the conformation of prions or of Alzheimer's disease.
- lipids mainly lies in their ability to serve as solvents for proteins (Singer & Nicolson, Science 1 75 (1 972), 720-731). However, this is certainly not their only role.
- the different types of lipids are not only arranged in a fluid double layer, but are also asymmetrically distributed over the exoplasmic and cytoplasmic membrane areas (Bretscher and Raff, Nature 258 (1 975), 43-49; Roelofsen & Op den Kamp, Plasma Membrane Phospholipid Asymmetry and its Maintenance: The Human Erythrocyte as a Model 1-7-46 (1,994)).
- lipids are also organized in a certain way and thus perform more regulatory tasks than previously known (Glaser, Curr. Op. Struct. Biol. 3 (1 993), 475-481, Thomas et al., J. Cell Biol. 1 25 (1 994), 1 95-802, Kusumi & Sako, Curr. Opin. Cell Bio. 8 (1 996), 566-574). It has now been shown that a lateral organization of lipids results from the connection of sphingolipids and cholesterol to moving clods or rafts, to which proteins can specifically attach themselves within the double layer. The existence of such sphingolipid-cholesterol rafts leads to a fundamentally different assessment of the membrane organization and allows new insights into the function of cell membranes.
- Sphingolipid head groups which occupy larger areas of the plane of the exoplasmic part of the membrane than the carbon chains of the hydrogen Lipids in the membrane layer, creating gaps that are filled by cholesterol molecules that act as spacers, so to speak (FIG. 1B).
- a close connection of these sphingolipid cholesterol clusters on the exoplasmic part of the membrane allows them to function as an overall arrangement within the membrane double layer.
- the sphingolipids normally have a long fatty acid (C 20 -C 26 ) attached to the sphingosine base via an amide bond, which due to the length of the fatty acid connects it to the cytoplasmic part of the double layer of the membrane can kick.
- the object of the present invention was therefore to provide a possibility of being able to have a positive effect on diseases such as Alzheimer's disease or other diseases in which a change in proteins on sphingolipid-cholesterol rafts takes place.
- this object is achieved by the use of cholesterol-lowering agents for the prophylaxis or treatment of diseases which are based on a change in the conformation of prions, or of
- cholesterol-lowering agent As a cholesterol-lowering agent, all agents can are used, which lower the cholesterol content in the blood and can be used for this purpose for the prophylaxis of other diseases, especially arteriosclerosis and heart attack.
- cholesterol-lowering agents include the active ingredient lovastatin (Mevinacor, mevinolin, Monacolin-K, MK-803), as well as further medicaments for hypercholesterolemia, such as pravastatin sodium, simvastatin, bezafibrate, clofibrate, etofyllinclofibrate, xenofibrate, gemfibrozyl, etipololate, etofolibrate, etofolibrate HCI, colestyramine, xantinol nicotinate, icositol nicotinate, probucol and the like.
- Lovastatin inhibits cholesterol biosynthesis based on mevalonic acid. It is already used as a medicine for hypercholesterolemia, where it is administered in doses of up to 20 mg / day.
- the dosages of cholesterol-lowering agents according to the invention are known or can be easily determined by a person skilled in the art.
- Another possible way to lower cholesterol is to influence the regulation of cholesterol metabolism.
- the distribution of cholesterol on sphingolipid cholesterol rafts is much higher than its distribution on areas where there are no rafts. In the endoplasmic reticulum, where the cellular cholesterol content is perceived and regulated, there are practically none. Rafts. Sphingolipid cholesterol rafts do not flow back from the Golgi to the endoplasmic reticulum. Lowering cholesterol initially affects cholesterol not found in rafts, which means that less cholesterol flows back into the endoplasmic reticulum. For example, by reducing the sphingolipid content, it would then be possible to simultaneously lower the cholesterol synthesis in the cell, since more cholesterol can flow back into the endoplasmic reticulum. This can be done, for example, by sphingolipid synthesis inhibitors.
- the scrapie prion protein PrP sc is the only known component of a transferable prion. It is derived from a protein PrP c which is normally anchored to glycosylphosphatidylinositol (GPI) and which is expressed in neurons, a change in the conformation of PrP c resulting in the prion protein PrP sc , which is protease-resistant. This conformational change probably takes place on sphingolipid-cholesterol rafts. The conformational change appears to be dependent on the GPI anchorage, since chimeric proteins that contain their own transmembrane domain are not subject to the conformational change.
- GPI glycosylphosphatidylinositol
- PrP c is insoluble in Triton X-100 at 4 ° C during the conformational change, and depletion of cellular cholesterol prevents the formation of PrP sc .
- PrP ° can be introduced into the cell through clathrin-coated vesicles using endocytosis, presumably due to binding to a previously unknown transmembrane protein with a so-called coated pit signal. This bond may keep PrP c away from the rafts where the as yet unexplained PrP c -PrP sc transformation appears to take place.
- Aß amyloid precursor protein
- APP amyloid precursor protein
- the split from APP to Aß happens in two steps. First, a so-called ⁇ -cleavage generates a fragment of 10 kDa from APP, which is then cleaved again within the transmembrane domain (> v-cleavage), with Aß being formed. Like PrP c , part of the APP is insoluble in Triton X-1 00 neurons, a property that also has GPI-anchored and transmembrane proteins that bind to sphingolipid rafts. Exactly where A /?
- Peptide is located in the APP molecule exactly where it can be expected if it is assumed that this region binds to a glycosphingolipid.
- Another interesting connection to the sphingolipid cholesterol rafts is the recent discovery that Aß binds to the glycanation end-product receptor (Yan et al., Nature 382 (1 996), 685-691), which were found to associate them with DIGs and caveoles in endothelial cells (Lisanti et al., Developm. Biol. 6 (1 995), 47-58).
- cholesterol-lowering agents has a positive effect on the abovementioned diseases. This may be due to a reduction in the number of rafts in the plasma membranes and thus a reduction in the number of possible anchor points at which a conformational change in proteins then takes place.
- cholesterol-lowering agents have a positive effect on Alzheimer's disease or diseases, such as Creutzfeld-Jacob Illness, which affects, is the first time that a treatment option has emerged that attacks the cause of the disease.
- sphingolipid-cholesterol rafts results in sub-compartmentalization on the cell membrane, which leads to the formation of different structures, i.e. rafts of different sizes, and 15 spaces without a raft structure.
- T cell receptor signaling processes are immunoglobulin E signaling processes in allergic reactions, T cell receptor signaling processes, LPS endotoxin signaling processes, signaling processes of endothelial NO synthase, signaling processes by tyrosine kinases, such as Lyn and Fyn, which are doubly aylated and via trimeric G -Proteins that contain doubly aylated subunits and transmit signals via GPI-anchored proteins.
- tyrosine kinases such as Lyn and Fyn
- Another object of the present invention is therefore the use of cholesterol-lowering agents for influencing signal transduction processes on the cell membrane.
- Fig. 1 shows a cell membrane in cross section.
- A shows a section with
- B shows an enlargement of a sphingolipid-cholesterol raft.
- Fig.2 shows that the removal of cholesterol reduces production
- Lovastatin / Mevalonat were cultivated. Cyclodextrin was added for 0, 5 and 20 min (0, 20, 5). b shows an immunoprecipitation assay similar to a, with CD cholesterol added for the indicated time in minutes (0 and 15, respectively), c shows the relative Aß secretion in cells in which the cholesterol was removed by lovastatin and cyclodextrin or was added again, in comparison with untreated control cells (mean from 3-1 1 experiments). The digits next to cyclodextrin and CD cholesterol indicate the time in minutes.
- Figure 3 shows that cholesterol removal reduces APP attachment to DIGs. Neurons were extracted according to Example 2 and centrifuged through an OptiPrep gradient, after which larger molecules and complexes (A? -DIG) are more at the upper end of the test tube (above) and uncomplexed, smaller ones
- - Depletion or + Depletion refers to the cholesterol that has been removed (+) or not removed (-) as described above.
- the neurons were then infected for 1 h at 37 ° C. and 5% CO 2 with recombinant SFV, which codes for the human APP 695 protein, as is already known from the prior art.
- the cells were incubated in Lovastatin / Mevalonate for 2 hours and then incubated for 5-20 min with 5 mM methyl /? - cyclodextrin (Sigma) in a methionine-free labeling medium (MEM with 1/10 N2 addition).
- MEM methionine-free labeling medium
- the cells were labeled with 1 50 ⁇ C ⁇ [ 35 S] methionine for 2.5 hours.
- Lovastatin inhibits cholesterol biosynthesis in the presence of small amounts of mevalonate.
- Methyl-S-Cyclodextrin specifically removes cellular cholesterol.
- the culture medium was collected and cell extracts were prepared (2% NP-40, 0.2% SDS, 5 mM EDTA, with protease inhibitors as an additive).
- the immunoprecipitates were on A-Sepharose
- Extracts of neuronal cells were prepared as in Example 1, except that they were pulse-labeled for 20 minutes and then chased in normal medium for 100 minutes. The cells were then on ice for 30 min with 1% Triton X-100 in TEX (1 50 mM NaCl, 50 mM Tris pH 7.4, 2 mM EDTA, 2 mM DTT, 25 ⁇ g / ml each from chymostatin, leupeptin , Antipain, Pepstatin A) extracted. The extracts were then mixed with an equivalent amount of OptiPrep (Nycomed) and overlaid in TEX with a gradual gradient of 30%, 25% and 3% OptiPrep. The samples were then centrifuged at 4 ° C.
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Application Number | Priority Date | Filing Date | Title |
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DE1997116120 DE19716120A1 (de) | 1997-04-17 | 1997-04-17 | Verwendung von cholesterinsenkenden Mitteln |
DE19716120.0 | 1997-04-17 |
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WO1998047518A1 true WO1998047518A1 (de) | 1998-10-29 |
WO1998047518A9 WO1998047518A9 (de) | 1999-03-25 |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999048488A2 (en) * | 1998-03-23 | 1999-09-30 | Children's Medical Center Corporation | Methods for decreasing beta amyloid protein |
WO2000028981A2 (en) * | 1998-11-13 | 2000-05-25 | Nymox Corporation | Methods for treating, preventing, and reducing the risk of the onset of alzheimer's disease using an hmg coa reductase inhibitor |
WO2001032161A2 (en) * | 1999-11-04 | 2001-05-10 | Andrx Corporation | Use of a hmg-coa reductase inhibitor for treating amyloid beta precursor disorders |
EP1370210A2 (de) * | 2001-02-07 | 2003-12-17 | The McLean Hospital Corporation | Cholesterinsenkende mittel als behandlung gegen psychische und kognitive störungen |
EP1584333A2 (de) * | 1998-01-28 | 2005-10-12 | Warner-Lambert Company LLC | Verwendung von Acetylcoenzyme A Inhibitoren zur Behandlung von Alzheimer |
EP1051161B1 (de) * | 1998-01-28 | 2006-03-22 | Warner-Lambert Company Llc | Verfahren zur behandlung von alzheimerschen krankheit |
US8679534B2 (en) | 1997-12-12 | 2014-03-25 | Andrx Labs, Llc | HMG-CoA reductase inhibitor extended release formulation |
EP3603649A1 (de) * | 2018-07-31 | 2020-02-05 | Medday Pharmaceuticals | Verfahren zur behandlung von prionerkrankungen |
US10881694B2 (en) * | 2003-11-14 | 2021-01-05 | Adil A. KHAN | In vitro model for neuronal death |
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Cited By (19)
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US8679534B2 (en) | 1997-12-12 | 2014-03-25 | Andrx Labs, Llc | HMG-CoA reductase inhibitor extended release formulation |
EP1584333A2 (de) * | 1998-01-28 | 2005-10-12 | Warner-Lambert Company LLC | Verwendung von Acetylcoenzyme A Inhibitoren zur Behandlung von Alzheimer |
EP1584333A3 (de) * | 1998-01-28 | 2009-04-29 | Warner-Lambert Company LLC | Verwendung von Acetylcoenzyme A Inhibitoren zur Behandlung von Alzheimer |
EP1051161B1 (de) * | 1998-01-28 | 2006-03-22 | Warner-Lambert Company Llc | Verfahren zur behandlung von alzheimerschen krankheit |
WO1999048488A3 (en) * | 1998-03-23 | 2000-06-22 | Childrens Medical Center | Methods for decreasing beta amyloid protein |
US6080778A (en) * | 1998-03-23 | 2000-06-27 | Children's Medical Center Corporation | Methods for decreasing beta amyloid protein |
WO1999048488A2 (en) * | 1998-03-23 | 1999-09-30 | Children's Medical Center Corporation | Methods for decreasing beta amyloid protein |
US6440387B1 (en) | 1998-03-23 | 2002-08-27 | Children's Medical Center Corporation | Methods for determining risk of Alzheimer's disease |
WO2000028981A3 (en) * | 1998-11-13 | 2000-11-09 | Nymox Corp | Methods for treating, preventing, and reducing the risk of the onset of alzheimer's disease using an hmg coa reductase inhibitor |
AU771254B2 (en) * | 1998-11-13 | 2004-03-18 | Nymox Corporation | Methods for treating, preventing, and reducing the risk of the onset of Alzheimer's disease using an HMG CoA reductase inhibitor |
US6472421B1 (en) | 1998-11-13 | 2002-10-29 | Nymox Corporation | Methods for treating, preventing, and reducing the risk of the onset of alzheimer's disease using an HMG CoA reductase inhibitor |
WO2000028981A2 (en) * | 1998-11-13 | 2000-05-25 | Nymox Corporation | Methods for treating, preventing, and reducing the risk of the onset of alzheimer's disease using an hmg coa reductase inhibitor |
WO2001032161A3 (en) * | 1999-11-04 | 2002-03-14 | Andrx Corp | Use of a hmg-coa reductase inhibitor for treating amyloid beta precursor disorders |
WO2001032161A2 (en) * | 1999-11-04 | 2001-05-10 | Andrx Corporation | Use of a hmg-coa reductase inhibitor for treating amyloid beta precursor disorders |
EP1370210A2 (de) * | 2001-02-07 | 2003-12-17 | The McLean Hospital Corporation | Cholesterinsenkende mittel als behandlung gegen psychische und kognitive störungen |
EP1370210A4 (de) * | 2001-02-07 | 2004-08-18 | Mclean Hospital Corp | Cholesterinsenkende mittel als behandlung gegen psychische und kognitive störungen |
US10881694B2 (en) * | 2003-11-14 | 2021-01-05 | Adil A. KHAN | In vitro model for neuronal death |
EP3603649A1 (de) * | 2018-07-31 | 2020-02-05 | Medday Pharmaceuticals | Verfahren zur behandlung von prionerkrankungen |
WO2020025598A1 (en) | 2018-07-31 | 2020-02-06 | Medday Pharmaceuticals | Method for treating prion diseases |
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Publication number | Publication date |
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WO1998047518A9 (de) | 1999-03-25 |
DE19716120A1 (de) | 1998-10-22 |
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