WO2021051272A1 - Utilisation de citrate de bismuth potassique dans la préparation d'un médicament pour la prévention ou le traitement de maladies neurodégénératives - Google Patents

Utilisation de citrate de bismuth potassique dans la préparation d'un médicament pour la prévention ou le traitement de maladies neurodégénératives Download PDF

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WO2021051272A1
WO2021051272A1 PCT/CN2019/106210 CN2019106210W WO2021051272A1 WO 2021051272 A1 WO2021051272 A1 WO 2021051272A1 CN 2019106210 W CN2019106210 W CN 2019106210W WO 2021051272 A1 WO2021051272 A1 WO 2021051272A1
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drug
protein
disease
neurodegenerative diseases
tau protein
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PCT/CN2019/106210
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English (en)
Chinese (zh)
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续旭
蔡楠
李梅婷
顾粮
杨朋
吴志兵
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深圳大学
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Priority to PCT/CN2019/106210 priority Critical patent/WO2021051272A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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 invention belongs to the field of medicine, and specifically relates to the application of bismuth potassium citrate in the preparation of medicines for preventing and treating neurodegenerative diseases.
  • the existing potassium bismuth citrate is used for the treatment of gastric and duodenal ulcers, as well as compound ulcers, multiple ulcers, anastomotic ulcers and erosive gastritis.
  • This product is combined with antibiotics to eradicate Helicobacter pylori. It is used for Helicobacter pylori-related gastric and duodenal ulcers and chronic gastritis, gastric MALT lymphoma, early postoperative gastric cancer, gastroesophageal reflux disease and functional dyspepsia. It can also be combined with drugs that inhibit gastric acid secretion (proton pump inhibitors and H2 receptor antagonists) to form a quadruple program as a remedial treatment for failure to eradicate Helicobacter pylori.
  • the purpose of the present invention is to provide a new use of bismuth potassium citrate, so as to solve the technical problem of insufficient application development of bismuth potassium citrate in the prior art.
  • the present invention provides the application of bismuth potassium citrate in the preparation of drugs for the prevention and treatment of neurodegenerative diseases.
  • the neurodegenerative diseases include Alzheimer’s disease, amyotrophic lateral sclerosis/Parkinson’s syndrome-dementia complex, argyrophilic granular dementia, cortical basal degeneration, Creutzfeldt-Jakob disease, boxer Dementia, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia with Parkinson's syndrome linked to chromosome 17, Gersch-Schatz disease, Hallerwalden-Spar Pick’s disease, dystrophic myotonia, C Niemann-Pick disease, non-Guam motor neuron disease with neurofibrillary tangles, Pick’s disease, Parkinson’s syndrome after encephalitis, prion protein, brain starch Protein-like vascular disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary dementia only, whole brain glial cell Tau protein disease, cerebral am
  • the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting abnormal aggregation of Tau protein.
  • the drug for preventing and treating neurodegenerative diseases is a drug that inhibits the overexpression of Tau protein in cells.
  • the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting hyperphosphorylation of Tau protein in cells.
  • the drug that inhibits the hyperphosphorylation of Tau protein in the cell is a drug that activates the expression of PP2A.
  • the abnormal aggregation of Tau protein includes oligomerization or fibrosis caused by gene mutation or abnormal modification.
  • the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting abnormal aggregation of A ⁇ protein.
  • the drug for preventing and treating neurodegenerative diseases is a drug for reducing the secretion of A ⁇ protein.
  • the drug for preventing and treating neurodegenerative diseases is a drug that inhibits the expression of APP and BACE1.
  • the abnormal aggregation of A ⁇ protein includes aggregation of ⁇ -amyloid caused by abnormal expression of powder-like precursor protein and ⁇ -secretase.
  • the present invention has developed a new use of bismuth potassium citrate, which is specifically applied in the treatment of neurodegenerative diseases; the original potassium bismuth citrate is mainly used for the treatment of ulcers, and ulcers are far harmful to the human body. Far inferior to neurodegenerative diseases, so the development of this application has very important value.
  • Figure 1 is the chemical structural formula of potassium bismuth citrate according to an embodiment of the present invention.
  • Fig. 2 is a diagram showing the effect of in vitro anti-Tau protein aggregation effect of potassium bismuth citrate according to an embodiment of the present invention
  • Fig. 3 is a transmission electron micrograph of the inhibition of Tau protein fibrosis by potassium bismuth citrate according to an embodiment of the present invention
  • FIG. 4 is a diagram showing the docking results of potassium bismuth citrate and Tau protein molecules according to an embodiment of the present invention
  • FIG. 5 is a graph showing the results of changes in the expression of Tau protein, pS396-Tau, and pS404-Tau after potassium bismuth citrate acts on SH-SY5Y/Tau and HEK293/Tau cells according to an embodiment of the present invention
  • FIG. 6 is a graph showing the results of changes in the expression of PP2A ⁇ and PP2A ⁇ + ⁇ protein after the effect of potassium bismuth citrate on SH-SY5Y/Tau and HEK293/Tau cells according to an embodiment of the present invention
  • Fig. 7 is a graph showing changes in APP, BACE1 and A ⁇ protein expression levels after the treatment of N2a-sw-APP695 cells by potassium bismuth citrate according to an embodiment of the present invention.
  • Tau protein is a microtubule-associated protein encoded by the MAPT gene on chromosome 17. It maintains normal axon transport and microtubule structural stability under physiological conditions. Its basic function is to promote the assembly of tubulin into microtubules and further stabilize it. Assembled microtubules. Under normal circumstances, there are generally two to three amino acids on the Tau protein that are phosphorylated. When the Tau protein undergoes abnormal hyperphosphorylation, gene mutation or other molecular induction, the Tau protein will depolymerize from the microtubules and form Neuronal fibrillary tangles (Neuronal fibrillary tangles) affect the basic morphology and function of neurons, thereby impairing the normal performance of the nervous system.
  • Neuronal fibrillary tangles Neuronal fibrillary tangles
  • Tauopathies are a group of degenerative diseases of the nervous system closely related to cognitive dysfunction that have gradually received attention in recent years. These diseases associated with abnormal phosphorylation of Tau protein and defects in its coding genes are collectively referred to as Tau protein diseases, including Alzheimer’s disease (Alzheimer’s disease).
  • Alzheimer's disease amyotrophic lateral sclerosis/parkinsonism-dementia complex (Amyotrophic lateral sclerosis/parkinsonism-dementia complex), Argyrophilic grain dementia, Corticobasal degeneration, Creutzfeldt-Jakob disease), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification calcification), Down’s syndrome, Frontotemporal dementia with Parkinson’s syndrome linked to chromosome 17 dementia with parkinsonism linked to chromosome17), Gerstmann-Straussler-Scheinker disease), Hallervorden-Spatz disease (Hallervorden-Spatz disease), Myotonic dystrophy (Myotonic dystrophy), Niemann-Pick disease type C (Niemann-Pick disease type C), Non-Guamanian motor neuron disease with neurofibrillary tangles (Non-Guamanian motor neuron disease) disease with neurofibri
  • Tau protein diseases have diverse phenotypes and clinical features, and they all co-exist in the form of fibrils/filaments/fibrils (for example, twisted, linear or paired helices) insoluble, hyperphosphorylated Tau nerves
  • the fibrils are tangled.
  • the clinical symptoms, signs, and neuroimaging changes of the above diseases are quite different, their common feature is the deposition of abnormal Tau protein in the brain. Therefore, they are re-assigned at the level of protein research, forming the "Tau protein disease”. Eye-catching disease groups. By inhibiting the aggregation of Tau protein and reducing the expression of Tau protein and multi-site phosphorylated Tau protein in cells, effective treatment of Tau protein diseases can be achieved.
  • ⁇ -amyloid is a normal metabolite of the body, which is composed of ⁇ -amyloid precursor protein (amyloid ⁇ -protein precursor, APP) through ⁇ -secretase ( ⁇ -site APP-cleaving enzyme, ⁇ -secretase, BACE) and ⁇ -secretase cleavage.
  • APP ⁇ -amyloid precursor protein
  • BACE ⁇ -secretase
  • APP's sequential ⁇ -secretase (BACE1) abnormal cleavage produces oligomers, which are surrounded by abnormal neurons and axons, resulting in increased A ⁇ production or decreased clearance.
  • a ⁇ has neurotoxicity. When its content increases and cannot be completely metabolized by cells, A ⁇ senile plaques will be deposited in large amounts in the cells, which will eventually promote the early pathological process of neurofibrillary tangles or neuronal death.
  • AD Alzheimer’s disease
  • cerebral amyloid angiopathy the diseases related to A ⁇ deposition in the brain, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy.
  • AD is a common neurodegenerative disease, the clinical manifestations are progressive memory loss and cognitive impairment.
  • the excessive increase of A ⁇ in the brain tissue leads to oxidative stress and inflammation in the nervous system, which ultimately leads to neuronal apoptosis and the occurrence of AD. Therefore, it is generally believed that reducing the content of A ⁇ in the whole brain by inhibiting the production of A ⁇ or promoting the clearance of A ⁇ will effectively prevent or treat AD.
  • the embodiment of the present invention provides an application of bismuth potassium citrate, which is to use bismuth potassium citrate for the preparation of drugs for the prevention and treatment of neurodegenerative diseases.
  • the neurodegenerative diseases include Alzheimer’s disease, amyotrophic lateral sclerosis/Parkinson’s syndrome-dementia complex, argyrophilic granular dementia, cortical basal degeneration, Creutzfeldt-Jakob disease, boxer Dementia, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia with Parkinson's syndrome linked to chromosome 17, Gersch-Schatz disease, Hallerwalden-Spar Pick’s disease, dystrophic myotonia, C Niemann-Pick disease, non-Guam motor neuron disease with neurofibrillary tangles, Pick’s disease, Parkinson’s syndrome after encephalitis, prion protein, brain starch Protein-like vascular disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary dementia only, whole brain glial cell Tau protein disease, cerebral amy
  • the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting abnormal accumulation of Tau protein. More specifically, the drug for preventing and treating neurodegenerative diseases is a drug that inhibits the overexpression of Tau protein in cells. More specifically, the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting hyperphosphorylation of Tau protein in cells. More specifically, the drug that inhibits hyperphosphorylation of Tau protein in a cell is a drug that activates PP2A expression. More specifically, the abnormal aggregation of Tau protein includes oligomerization or fibrosis caused by gene mutation or abnormal modification. Under normal circumstances, there are generally two to three amino acids on the Tau protein that are phosphorylated.
  • the Tau protein When the Tau protein undergoes abnormal hyperphosphorylation, gene mutation or other molecular induction, the Tau protein will depolymerize from the microtubules and form Neurofibrillary tangles affect the basic morphology and function of neurons, thereby impairing the normal functioning of the nervous system.
  • the potassium bismuth citrate of the present invention inhibits the overexpression of Tau protein, so that the Tau protein cannot reach the aggregation concentration; on the other hand, it inhibits the hyperphosphorylation of Tau protein in the cell by activating PP2A expression, and fundamentally alleviates the abnormality of Tau protein. Gather.
  • the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting abnormal aggregation of A ⁇ protein. More specifically, the drug for preventing and treating neurodegenerative diseases is a drug for reducing the secretion of A ⁇ protein. Furthermore, the drug for preventing and treating neurodegenerative diseases is a drug for inhibiting the expression of APP and BACE1.
  • APP protein is cleaved by BACE1 enzyme to form A ⁇ protein, and inhibiting the expression of APP and BACE1 also inhibits the formation of A ⁇ protein. That is, by inhibiting the expression of APP and BACE1 to inhibit the secretion of A ⁇ protein, and finally control the concentration of A ⁇ protein to inhibit the abnormal aggregation of A ⁇ protein.
  • the abnormal aggregation of A ⁇ protein includes the aggregation of A ⁇ protein caused by the abnormal expression of powder-like precursor protein and ⁇ -secretase.
  • bismuth potassium citrate can significantly reduce the expression of Tau protein in SH-SY5Y/Tau and HEK293/Tau cells and the phosphorylation level of Tau protein at Ser396 and Ser404 sites, and increase the expression of PP2A ⁇ and PP2A ⁇ + ⁇ ; At the same time, it can reduce the expression of A ⁇ , APP and BACE1 in N2a-sw-APP695 cells, and is concentration-dependent.
  • bismuth potassium citrate can inhibit Tau protein aggregation, reduce Tau protein expression, reduce multi-site Tau protein phosphorylation, and reduce the expression of A ⁇ , APP and BACE1, which can be used to prevent or treat Tau protein or Neurodegenerative diseases caused by abnormal aggregation of A ⁇ protein.
  • the specific test methods and test data are described in detail in the embodiments.
  • Bismuth potassium citrate, heparin sodium, and thioflavin T were purchased from Sigma; high glucose DMEM medium, F12-DMEM medium, opti-MEN medium, penicillin, streptomycin, and fetal bovine serum were purchased from Gibco Company; Tau, pS396-Tau, pS404-Tau, PP2A ⁇ , PP2A ⁇ + ⁇ , A ⁇ , APP, BACE1, ⁇ -actin antibodies were purchased from Abcam; ECL luminescent solution was purchased from Thermo Fisher Scientific, and other conventional chemical reagents were purchased From Sigma.
  • Bismuth potassium citrate inhibits Tau protein aggregation induced by heparin
  • Tau protein can be induced by heparin in vitro and self-aggregate to form fibers, thereby mimicking the pathological process of abnormal accumulation of Tau protein in vivo to produce neurofibrillary tangles.
  • Thioflavin T (ThT) can bind to the ⁇ structure of the fiber to emit fluorescence, so the fibrosis process of Tau protein can be tracked by the fluorescence value of ThT.
  • the transmission electron microscope can directly observe the fibrosis of the Tau protein sample, which can further verify the results of the ThT fluorescence experiment. Take 5 ⁇ L of each sample in the Tau protein ThT experiment and drop it on a 230 mesh copper screen. Then use filter paper to absorb the excess sample. After drying, drip 5 ⁇ L of uranyl acetate respectively. After dyeing for 1 minute, absorb the excess liquid. After drying, place it on Observe and take pictures in a transmission electron microscope (NIPPON TEKNO, JEM-1230). The results are shown in Figure 3. In the control group, dense Tau protein fibers can be observed under the transmission electron microscope. After the addition of bismuth potassium citrate, the Tau protein fibers are sparse and broken, indicating that bismuth potassium citrate can effectively block Tau protein. Fiber formation.
  • the bismuth potassium citrate molecule binds to the hydrophobic pocket of Tau protein and is surrounded by His-362, Pro-364, Gly-367, Asn-368 and Lys-369, and more importantly, citrate Potassium bismuth forms four hydrogen bonds with His-362, Asn-368 and Lys-369, with bond lengths of 3.30, 2.68, 2.63 and 2.75 ⁇ , respectively. All these interactions can help bismuth citrate anchor in the R3 domain of Tau protein, block the aggregation of Tau protein, and then inhibit the formation of Tau protein fibers, which can effectively reduce neurotoxicity. It has prevention and treatment of Tau. Potential for neurodegenerative diseases caused by protein aggregation.
  • Bismuth potassium citrate reduces the phosphorylation level of multiple sites of Tau protein in SH-SY5Y/Tau and HEK293/Tau cells
  • SH-SY5Y/Tau and HEK293/Tau cells were seeded on a culture plate, the supernatant was discarded after the cells adhered, and serum-free medium containing bismuth potassium citrate was added for 24h.
  • the total cell protein was extracted with cell lysate, and the expression of phosphorylated Tau protein in the cell was detected by Western Blot method.
  • Potassium bismuth citrate increases PP2A ⁇ and PP2A ⁇ + ⁇ protein expression in SH-SY5Y/Tau and HEK293/Tau cells
  • SH-SY5Y/Tau and HEK293/Tau cells were seeded on a culture plate, the supernatant was discarded after the cells adhered, and serum-free medium containing bismuth potassium citrate was added for 24h.
  • the cell lysate was used to extract the total cell protein, and the expression of PP2A ⁇ and PP2A ⁇ + ⁇ protein in the cells was detected by Western Blot method.
  • Bismuth potassium citrate reduces the expression of A ⁇ , APP and BACE1 protein in N2a-sw-APP695 cells
  • the N2a-sw-APP695 cells were inoculated into the culture plate, and the supernatant was discarded after the cells adhered, and the serum-free medium containing bismuth potassium citrate was added for 24h.
  • the cell lysate was used to extract total cell protein, and the expression of A ⁇ , APP and BACE1 protein in the cell was detected by Western Blot method.
  • Potassium bismuth citrate can effectively inhibit heparin-induced Tau protein aggregation and effectively hinder the formation of Tau protein fibers.
  • bismuth potassium citrate can bind to the core structure of the Tau protein monomer, which assisted in proving the binding effect and potential binding sites between bismuth potassium citrate and Tau protein.
  • potassium bismuth citrate can enhance the expression of PP2A ⁇ and PP2A ⁇ + ⁇ in SH-SY5Y/Tau and HEK293/Tau cells, thereby inhibiting the phosphorylation level of Tau protein at Serine 396 and 404.
  • bismuth potassium citrate can also reduce the expression of APP, BACE1 and A ⁇ protein in N2a-sw-APP695 cells.
  • Bismuth potassium citrate can effectively inhibit Tau protein aggregation in vitro, thereby inhibiting the formation of neurofibrillary tangles.
  • Potassium bismuth citrate can increase the expression of PP2A ⁇ and PP2A ⁇ + ⁇ in SH-SY5Y/Tau and HEK293/Tau cells, thereby reducing the phosphorylation level of intracellular Tau protein at Serine 396 and 404.
  • Bismuth potassium citrate can reduce the expression of A ⁇ protein, APP and BACE1 protein in N2a-sw-APP695 cells.
  • bismuth potassium citrate can inhibit Tau protein aggregation, reduce the phosphorylation level of Tau protein at multiple sites in the cell, and reduce the expression of A ⁇ . It can be used to prevent or treat abnormal aggregation, hyperphosphorylation or Tau protein. Neurodegenerative diseases caused by abnormal expression of A ⁇ protein.

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Abstract

L'invention concerne une utilisation du citrate de bismuth potassique dans la préparation d'un médicament pour la prévention ou le traitement d'une maladie neurodégénérative. Par rapport à l'état de la technique, une nouvelle utilisation du citrate de bismuth potassique est développée, en particulier une utilisation dans le traitement de maladies neurodégénératives. Le citrate de bismuth potassique d'origine est principalement utilisé pour traiter des ulcères, mais le danger posé sur le corps humain par des ulcères est inférieur à celui posé par les maladies neurodégénératives, et par conséquent le développement de la présente utilisation maintient une valeur très importante.
PCT/CN2019/106210 2019-09-17 2019-09-17 Utilisation de citrate de bismuth potassique dans la préparation d'un médicament pour la prévention ou le traitement de maladies neurodégénératives WO2021051272A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI238718B (en) * 2001-08-27 2005-09-01 Hedonist Biochmical Technologi Use of bismuth subgallate in inhibition of production of nitric oxide synthase
WO2009154819A2 (fr) * 2008-03-10 2009-12-23 The Charlotte-Mecklenburg Hospital Authority Traitement des affections et maladies inflammatoires au moyen de métal-thiols
US20110086911A1 (en) * 2009-10-13 2011-04-14 Monash University Novel bismuth(iii) nsaid compounds and methods for their use
AU2009225298A1 (en) * 2009-10-13 2011-04-28 Monash University Novel Bismuth(III) NSAID Compounds and Method for their Use
CN103313720A (zh) * 2010-11-08 2013-09-18 辛索尼克斯公司 用于调节生物活性剂的性质的含铋化合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI238718B (en) * 2001-08-27 2005-09-01 Hedonist Biochmical Technologi Use of bismuth subgallate in inhibition of production of nitric oxide synthase
WO2009154819A2 (fr) * 2008-03-10 2009-12-23 The Charlotte-Mecklenburg Hospital Authority Traitement des affections et maladies inflammatoires au moyen de métal-thiols
US20110086911A1 (en) * 2009-10-13 2011-04-14 Monash University Novel bismuth(iii) nsaid compounds and methods for their use
AU2009225298A1 (en) * 2009-10-13 2011-04-28 Monash University Novel Bismuth(III) NSAID Compounds and Method for their Use
CN103313720A (zh) * 2010-11-08 2013-09-18 辛索尼克斯公司 用于调节生物活性剂的性质的含铋化合物

Non-Patent Citations (1)

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Title
MA, YONGXIN; YU, ZHUO WEI: "Modern Studies on Dementia", 30 September 2008, SCIENCE AND TECHNOLOGY LITERATURE PRESS, CN, ISBN: 978-7-5023-6069-6, article MA, YONGXIN; YU, ZHUO WEI: "Tau Protein and Neurodegenerative Diseases", pages: 785 - 787, XP009526854 *

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