Application of VEGFR inhibitor in preparation of anti-Alzheimer's disease medicine

A technology of inhibitors and anti-inflammatory drugs, applied in the field of biopharmaceuticals, can solve problems such as aggravating disease progression, achieve the effects of restoring blood-brain barrier function, improving learning and memory ability and learning and memory behavior, and reducing blood-brain barrier permeability

Pending Publication Date: 2021-12-07
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that the pathological process of AD leads to pathological opening of the blood-brain barrier and increased permeability, allowing toxic substances in the blood to enter the brain, further aggravating the progression of the disease

Method used

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  • Application of VEGFR inhibitor in preparation of anti-Alzheimer's disease medicine
  • Application of VEGFR inhibitor in preparation of anti-Alzheimer's disease medicine
  • Application of VEGFR inhibitor in preparation of anti-Alzheimer's disease medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Alzheimer's disease causes functional damage to the blood-brain barrier

[0025] 1.1 Construction of physiological blood-brain barrier cell model

[0026] Using mouse-derived brain microvascular endothelial cells bEnd.3 as model cells, take 0.5 mL of bEnd.3 cell suspension in good growth state and inoculate it in a 12-well Transwell plate chamber with a pore size of 0.4 μm at a seeding density of 1×10 5 Each well, add 1.5mL fresh culture medium to the outer chamber, 37°C, 5% CO 2 The culture was continued for 15 days under the same conditions, and the fresh culture medium was replaced every other day. Use a cell resistance meter to measure the cell transmembrane resistance value, when the transmembrane resistance value is greater than 150 ohm square centimeter (Ω cm 2 ), which is a physiological blood-brain barrier cell model.

[0027] 1.2 Construction of pathological blood-brain barrier cell model

[0028] Taking bEnd.3 and PC-12 as model cells, take ...

Embodiment 2

[0032] Example 2 Axitinib up-regulates tight junction proteins in brain microvascular endothelial cells and restores blood-brain barrier function

[0033] 2.1 Immunofluorescence detection of tight junction protein expression in each group

[0034] Dilute bEnd.3 cells at 1 × 10 5 The density of cells / well was seeded in a 24-well plate with cell slides, and the cells were placed at 37°C, 5% CO 2 Cultured continuously for 7 days. The experimental groups were Normal group, AD group, AD+DPZ group, and AD+Axitinib group. Normal cultured cells in the Normal group; the latter three groups were treated with Aβ 1-42 Incubate for 24 hours, and then add donepezil or axitinib for another 24 hours. After that, the cells were washed 3 times with PBS, fixed with 4% formaldehyde, blocked with 10% bovine serum albumin for half an hour, added the primary antibody of tight junction protein Claudin-5 (1:200, monoclonal antibody, Invitrogen Company) and incubated overnight at 4°C . After wa...

Embodiment 3

[0038] Example 3 Axitinib regulates blood-brain barrier permeability in Alzheimer's disease model animals

[0039] 3.1 Construction of Alzheimer's disease model animals

[0040] Male C57 / BL6 mice (10w-12w) were selected as model animals, and Aβ at a concentration of 1 mg / mL was injected with the aid of a stereotaxic instrument. 1-42 The oligomer was injected into the hippocampus of the mouse (the injection coordinates were 2.3 mm behind the bregma, 1.8 mm to the right, and the depth was 2 mm), the injection volume was 5 μL / mouse, and the injection time was 5 minutes. After the injection, sutures were completed on the surface of the skull, and the operated mice were kept in an SPF-grade environment for one week to construct Alzheimer's disease model animals.

[0041] 3.2 After axitinib treatment, the penetration of Evans blue in the brain of Alzheimer's disease model animals was significantly reduced

[0042] Animals were grouped as follows: Normal group, AD group, AD+DPZ...

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Abstract

The invention discloses an application of a VEGFR inhibitor in preparation of an anti-Alzheimer's disease medicine. The VEGFR inhibitor is axitinib and an analogue thereof. It is found that axitinib has an unexpected curative effect on Alzheimer's disease, and Alzheimer's disease model animal in-vivo experiments prove that after administration of axitinib, beta-amyloid protein deposition in the brain of a model animal is significantly reduced, the content of acetylcholin esterase is reduced, the oxidative stress level and inflammatory response of the lesion part of the model animal are relieved, the learning and memory ability and learning and memory behaviors of the model animal on space and direction are improved, and the curative effect is obviously higher than that of a clinical first-line treatment drug donepezil. The axitinib and the analogue thereof provide a new means for clinical treatment of the Alzheimer's disease, and the axitinib and the analogue thereof are high in human body safety, low in price and easy to prepare. According to the invention, non-intracranial administration mode is adopted, safety is high, administration is convenient and fast, and patient compliance is high. The application of a VEGFR inhibitor in preparation of an anti-Alzheimer's disease medicine has wide market prospects and great social significance.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and in particular relates to the application of a VEGFR inhibitor in the preparation of anti-Alzheimer's disease drugs. Background technique [0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease, the main clinical manifestations are cognitive dysfunction and executive dysfunction. AD is highly age-dependent, and the incidence of AD will increase sharply with age. There are currently about 5 million AD patients worldwide, and this number will triple to 152 million by 2050. The main pathological features of AD include amyloid deposition, astrogliosis, hyperphosphorylation and accumulation of Tau protein, neuronal dystrophy, oxidative stress, dysregulation of biometal homeostasis, and decreased acetylcholine levels. Amyloid plaques formed by amyloid (Aβ) aggregation and neurofibrillary tangles formed by hyperphosphorylated Tau protein are two specific pathological features ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/454A61K31/496A61K31/506A61P25/28
CPCA61K45/00A61K31/454A61K31/496A61K31/506A61P25/28
Inventor 胡富强柯佳袁弘孟廷廷徐弋翀
Owner ZHEJIANG UNIV
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