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Use of axitinib and analogue thereof in preparation of blood-brain barrier permeability regulating agent

A technology of blood-brain barrier and axitinib, applied in the field of application of axitinib and its analogs in the preparation of blood-brain barrier permeability regulators

Active Publication Date: 2020-07-07
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it has not been reported that axitinib and its analogs have the effect of regulating the permeability of the blood-brain barrier

Method used

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  • Use of axitinib and analogue thereof in preparation of blood-brain barrier permeability regulating agent
  • Use of axitinib and analogue thereof in preparation of blood-brain barrier permeability regulating agent
  • Use of axitinib and analogue thereof in preparation of blood-brain barrier permeability regulating agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 The growth of brain glioma causes pathological damage to the blood-brain barrier and increases the permeability

[0055] 1. Physiological blood-brain barrier cell model construction

[0056] Brain microvascular endothelial cells bEnd.3 were used as blood-brain barrier model cells, and 1×10 5 For cell density per well, 0.5 mL of well-grown bEnd.3 cell suspension was inoculated in a 12-well Transwell plate chamber with a pore size of 0.4 μm, and 1.5 mL of fresh culture medium was added to the outer chamber. Replace the fresh medium every other day, and continue to incubate for 15 days at 37°C and 5% carbon dioxide. When the cell transmembrane resistance value is greater than 150 ohm·square centimeter (Ω·cm 2 ), a physiological blood-brain barrier cell model was obtained for evaluation.

[0057] 2. Pathological blood-brain barrier cell model construction

[0058] U87MG glioma cells were used as brain tumor model cells, and 2×10 5 For the cell density per...

Embodiment 2

[0067] Example 2 Axitinib acts on the vascular endothelial growth factor receptor (VEGFR), blocking the binding of vascular endothelial growth factor (VEGF) to the receptor in a dose-dependent manner

[0068] Taking the physiological blood-brain barrier constructed by method 1 in Example 1 as a model, exogenous vascular endothelial growth factor (VEGF) and different concentrations of axitinib were added to the Transwell chamber, and after 24 hours of drug action, the growth The Transwell chamber of bEnd.3 cells was taken out, washed three times with PBS, fixed with 4% formaldehyde, blocked with 10% bovine serum albumin for 30 minutes, added Claudin-5 primary antibody and incubated overnight at 4°C, and finally stained with fluorescently labeled The secondary antibody was incubated for 1 hour, and the nuclei were counterstained with DAPI. Laser confocal microscope was used to observe the expression of tight junction protein Claudin-5, and the results were as follows: Figure 7...

Embodiment 3

[0070] Example 3 Axitinib blocks the action site of vascular endothelial cell growth factor receptor, reduces the down-regulation of tight junction protein, and significantly reduces the degree of pathological damage to the blood-brain barrier

[0071] Using the pathological blood-brain barrier constructed by method 2 in Example 1 as a model, add axitinib to the Transwell chamber, and after 24 hours of drug action, transfer the Transwell chamber with bEnd.3 cells to another 12-well plate In this method, wash three times with PBS, fix with 4% formaldehyde, block with 10% bovine serum albumin for 30 minutes, add Claudin-5 primary antibody and incubate overnight at 4°C, and finally incubate with fluorescently-labeled secondary antibody for 1 hour, DAPI complex stained nuclei. Laser confocal microscope was used to observe the expression of tight junction protein Claudin-5, and the results were as follows: Figure 8 shown.

[0072] according to Figure 8 The results shown show t...

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Abstract

The invention relates to use of axitinib and an analogue thereof in preparation of a blood-brain barrier permeability regulating agent. The blood-brain barrier permeability regulating agent can reducethe blood-brain barrier permeability and promote the recovery of a blood-brain barrier function from a pathological damage state to an approximate physiological barrier state. The axitinib and the analogue thereof, by suppressing vascular endothelial cell growth factor-phosphatidylinositol kinase-protein kinase B signaling pathway, can reduce the down-regulating degree of pathological blood brainbarrier tightly attached protein Claudin-5 / Occludin and reduce the blood-brain barrier permeability. The blood-brain barrier permeability regulating agent can be used for treatment of related diseases that cause changes in the blood-brain barrier permeability.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to the new therapeutic application of axitinib and its analogs, in particular to the application of axitinib and its analogs in the preparation of blood-brain barrier permeability regulators. The blood-brain barrier permeability regulator can be used to treat related diseases that cause blood-brain barrier permeability changes. Background technique [0002] The blood-brain barrier is a special system to protect and maintain the function of the central nervous system. It is mainly composed of brain microvascular endothelial cells, tight junctions between endothelial cells, basement membrane, and glial cell foot processes around capillaries. The endothelial cells are extremely tight Connections are an important morphological basis of the blood-brain barrier. Most macromolecules and more than 98% of small molecule drugs cannot leak through the blood-brain barrier, and only a small number of nutri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61P25/00A61P25/28
CPCA61K31/4439A61P25/00A61P25/28A61P25/16
Inventor 胡富强温丽娟袁弘王凯孟廷廷
Owner ZHEJIANG UNIV
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