WO2021045717A1 - A pharmaceutical composition containing epibrassinolide (ebr) - Google Patents
A pharmaceutical composition containing epibrassinolide (ebr) Download PDFInfo
- Publication number
- WO2021045717A1 WO2021045717A1 PCT/TR2020/050810 TR2020050810W WO2021045717A1 WO 2021045717 A1 WO2021045717 A1 WO 2021045717A1 TR 2020050810 W TR2020050810 W TR 2020050810W WO 2021045717 A1 WO2021045717 A1 WO 2021045717A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- epibrassinolide
- ebr
- disease
- alzheimer
- Prior art date
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Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a pharmaceutical composition containing epibrassinolide (EBR) which exhibits neuro-protective effect in Alzheimer’s Disease models.
- EBR epibrassinolide
- Alzheimer’s Disease is a neurodegenerative disease. Clinical findings include severe language and memory impairment, disorientation, psychosocial regression, and behavioural symptoms. The disease is highly prevalent in individuals over 60- 65 years old. Being a critical problem in many countries in the world, Alzheimer’s Disease is known as the 5 th cause of death in older adults and an average of two hundred trillion dollars are spent annually for care of individuals with this type of dementia. Therefore, it is required to develop compositions that are protective against Alzheimer’s Disease and to prevent this disease.
- An objective of the present invention is to realize a pharmaceutical composition exhibiting neuro-protective effect against Alzheimer’s Disease.
- Another objective of the present invention is to realize a pharmaceutical composition containing epibrassinolide (EBR), which is a GSK3P inhibitor.
- EBR epibrassinolide
- the inventive pharmaceutical composition exhibits neuro-protective effect against Alzheimer’s Disease.
- the inventive pharmaceutical composition is a solution containing epibrassinolide (EBR) as stock solution and DMSO (dimethylsulphoxide) as solvent.
- EBR epibrassinolide
- DMSO dimethylsulphoxide
- the epibrassinolide (EBR) included within the content of the inventive pharmaceutical composition is an agent which is highly similar to steroid hormones in mammals structurally; it is a member of brassinosteroids (BR) which is one of plant growth hormones and an agent which induces apoptotic cell death in mammalian cancer cells.
- the EBR is an inhibitor of glycogen synthase kinase 3b (GSK3P) which is a serine/threonine kinase and like many GSK3 inhibitors, the EBR also has an effect on GSK3P homologue BIN2 inhibition, particularly on BR signal cascade.
- the EBR has an inhibiting characteristic on GSK3P by increasing Ser9 phosphorylation in different cancer cell lines. Changes occurring in GSK3P, signal mechanism are closely related to many diseases such as Alzheimer’s Disease, inflammation, type II diabetes and cancer, and GSK3P inhibitors have effect on reducing the pathological findings of these diseases.
- the dimethylsulphoxide (DMSO) included within the content of the inventive pharmaceutical composition enables biological use and utility of EBR as an organic solvent.
- the inventive method of obtaining pharmaceutical composition comprises steps of:
- a solution is obtained at a stock concentration of 5 mM by dissolving 10 milligrams of powder epibrassinolidine with a molecular weight of 480,7 g/mol within 4,1667 ml DMSO in a laminar flow medium. Then, 30 mM epibrassinolide is diluted from 5 mM stock solution.
- the pharmaceutical composition comprising the EBR -which is the inventive GSK3P inhibitor- is examined on wild type (N2) and mutant models (CL2120, CL2122, RB814, WM104, GMC101) of Caenorhabditis elegans (C. elegans) strains. According to the results obtained, it was detected that the pharmaceutical composition affected lifetime and fertility rates positively and no individual from the population decreased in all strains in the first six days after application of the composition. In a preferred embodiment of the invention, it is detected that the paralyzed condition caused by toxicity at 25°C in strains with a Alzheimer’s Disease model is eliminated by the pharmaceutical composition application.
- the pharmaceutical composition application it is detected that formation of reactive oxygen species (ROS) increasing in Alzheimer’s Disease model organisms recedes by the pharmaceutical composition application.
- ROS reactive oxygen species
- the pharmaceutical composition containing EBR creates an effective protective effect in C. elegans Alzheimer’s Disease models and achieves this effect GSK3 inhibition.
- the neuroprotective effect of EBR is also seen in cells with neuronal character such as SH-SY5Y (human) and PC 12 (rat) and the GSK3P phosphorylation mechanism is also inhibited in these cells.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Hospice & Palliative Care (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Psychiatry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a pharmaceutical composition containing epibrassinolide (EBR) which exhibits neuro-protective effect in Alzheimer's Disease models.
Description
A PHARMACEUTICAL COMPOSITION CONTAINING EPIBRASSIN OLIDE (EBR)
Technical Field
The present invention relates to a pharmaceutical composition containing epibrassinolide (EBR) which exhibits neuro-protective effect in Alzheimer’s Disease models.
Background of the Invention
Alzheimer’s Disease is a neurodegenerative disease. Clinical findings include severe language and memory impairment, disorientation, psychosocial regression, and behavioural symptoms. The disease is highly prevalent in individuals over 60- 65 years old. Being a critical problem in many countries in the world, Alzheimer’s Disease is known as the 5th cause of death in older adults and an average of two hundred trillion dollars are spent annually for care of individuals with this type of dementia. Therefore, it is required to develop compositions that are protective against Alzheimer’s Disease and to prevent this disease.
The United States patent document no. US7250551, an application in the state of the art, discloses treatment and diagnosis of individuals with neurodegenerative disorder such as Alzheimer’s Disease, method of inhibiting tau phosphorylation in an individual afflicted with Alzheimer’s Disease and inhibiting production of beta-amyloid (Ab) peptides in an individual affected by Alzheimer’s Disease.
Summary of the Invention
An objective of the present invention is to realize a pharmaceutical composition
exhibiting neuro-protective effect against Alzheimer’s Disease.
Another objective of the present invention is to realize a pharmaceutical composition containing epibrassinolide (EBR), which is a GSK3P inhibitor.
Detailed Description of the Invention
The inventive pharmaceutical composition exhibits neuro-protective effect against Alzheimer’s Disease.
The inventive pharmaceutical composition is a solution containing epibrassinolide (EBR) as stock solution and DMSO (dimethylsulphoxide) as solvent.
The epibrassinolide (EBR) included within the content of the inventive pharmaceutical composition is an agent which is highly similar to steroid hormones in mammals structurally; it is a member of brassinosteroids (BR) which is one of plant growth hormones and an agent which induces apoptotic cell death in mammalian cancer cells. In a preferred embodiment of the invention, the EBR is an inhibitor of glycogen synthase kinase 3b (GSK3P) which is a serine/threonine kinase and like many GSK3 inhibitors, the EBR also has an effect on GSK3P homologue BIN2 inhibition, particularly on BR signal cascade. The EBR has an inhibiting characteristic on GSK3P by increasing Ser9 phosphorylation in different cancer cell lines. Changes occurring in GSK3P, signal mechanism are closely related to many diseases such as Alzheimer’s Disease, inflammation, type II diabetes and cancer, and GSK3P inhibitors have effect on reducing the pathological findings of these diseases.
The dimethylsulphoxide (DMSO) included within the content of the inventive pharmaceutical composition enables biological use and utility of EBR as an organic solvent.
The inventive method of obtaining pharmaceutical composition comprises steps of:
- dissolving epibrassinolide within dimethylsulfoxide in a laminar flow medium; and
- diluting epibrassinolide from this solution.
In a preferred embodiment of the method of obtaining pharmaceutical composition, a solution is obtained at a stock concentration of 5 mM by dissolving 10 milligrams of powder epibrassinolidine with a molecular weight of 480,7 g/mol within 4,1667 ml DMSO in a laminar flow medium. Then, 30 mM epibrassinolide is diluted from 5 mM stock solution.
The pharmaceutical composition comprising the EBR -which is the inventive GSK3P inhibitor- is examined on wild type (N2) and mutant models (CL2120, CL2122, RB814, WM104, GMC101) of Caenorhabditis elegans (C. elegans) strains. According to the results obtained, it was detected that the pharmaceutical composition affected lifetime and fertility rates positively and no individual from the population decreased in all strains in the first six days after application of the composition. In a preferred embodiment of the invention, it is detected that the paralyzed condition caused by toxicity at 25°C in strains with a Alzheimer’s Disease model is eliminated by the pharmaceutical composition application. In another preferred embodiment of the invention, it is detected that formation of reactive oxygen species (ROS) increasing in Alzheimer’s Disease model organisms recedes by the pharmaceutical composition application. In a further embodiment of the invention, it is determined by chemotaxis assays that the disease model strains regain their motor skills and the amyloid b (Ab) deposits with Alzheimer’s Disease pathologic finding are eliminated by the pharmaceutical composition applications. The pharmaceutical composition containing EBR creates an effective protective effect in C. elegans Alzheimer’s Disease models and achieves this effect GSK3 inhibition. In another embodiment of the invention, the neuroprotective effect of EBR is also seen in cells with neuronal character
such as SH-SY5Y (human) and PC 12 (rat) and the GSK3P phosphorylation mechanism is also inhibited in these cells.
Within these basic concepts; it is possible to develop various embodiments of the inventive “Pharmaceutical Composition Containing Epibrassinolide (EBR)”; the invention cannot be limited to examples disclosed herein and it is essentially according to claims.
Claims
1. A pharmaceutical composition which is a solution containing epibrassinolide (EBR) as stock solution and DMSO (dimethylsulphoxide) as solvent, and exhibits neuro-protective effect against Alzheimer’s
Disease.
A method which is used for obtaining the pharmaceutical composition in the Claim 1; characterized by the steps of: dissolving epibrassinolide within dimethylsulfoxide in a laminar flow medium; and diluting epibrassinolide from this solution.
3. A method of obtaining pharmaceutical composition according to Claim 2; characterized in that a solution is obtained at a stock concentration of 5 mM by dissolving 10 milligrams of powder epibrassinolidine with a molecular weight of 480,7 g/mol within 4,1667 ml DMSO in a laminar flow medium. 4. A method of obtaining pharmaceutical composition according to Claim 3; characterized in that 30 mM epibrassinolide is diluted from 5 mM stock solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2019/13371 | 2019-09-05 | ||
| TR201913371 | 2019-09-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2021045717A1 true WO2021045717A1 (en) | 2021-03-11 |
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ID=74852141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2020/050810 WO2021045717A1 (en) | 2019-09-05 | 2020-09-05 | A pharmaceutical composition containing epibrassinolide (ebr) |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2021045717A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100204460A1 (en) * | 2007-08-22 | 2010-08-12 | Oklestkova Jana | Natural brassinosteroids for use for treating hyperproliferation, treating proliferative diseases and reducing adverse effects of steroid dysfunction in mammals, pharmaceutical composition and its use |
-
2020
- 2020-09-05 WO PCT/TR2020/050810 patent/WO2021045717A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100204460A1 (en) * | 2007-08-22 | 2010-08-12 | Oklestkova Jana | Natural brassinosteroids for use for treating hyperproliferation, treating proliferative diseases and reducing adverse effects of steroid dysfunction in mammals, pharmaceutical composition and its use |
Non-Patent Citations (2)
| Title |
|---|
| JULIEN CARL, MARCOUILLER FRANÇOIS, BRETTEVILLE ALEXIS, EL KHOURY NOURA B., BAILLARGEON JOANIE, HÉBERT SÉBASTIEN S., PLANEL EMMANUE: "Dimethyl sulfoxide induces both direct and indirect tau hyperphosphorylation", PLOS ONE, vol. 7, no. 6, 2012, pages e40020-1 - e40020-10, XP055802283 * |
| SANMARTÍN-SUÁREZ, C. ET AL.: "Antioxidant properties of dimethyl sulfoxide and its viability as a solvent in the evaluation of neuroprotective antioxidants", JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, vol. 63, no. 2, 2011, pages 209 - 215, XP028148461, DOI: 10.1016/j.vascn.2010.10.004 * |
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