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Application of ABCA1 agonist in preparation of medicine for treating eye diseases

A technology for eye diseases and agonists, applied in the field of ABCA1 agonists, can solve the problems of poor corneal penetration and short half-life

Active Publication Date: 2020-08-07
EYE & ENT HOSPITAL SHANGHAI MEDICAL SCHOOL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, nitric oxide has a short half-life and poor corneal penetration, so it is of great significance to study new drugs that act on the traditional aqueous humor outflow channel for the future antihypertensive treatment of glaucoma

Method used

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  • Application of ABCA1 agonist in preparation of medicine for treating eye diseases
  • Application of ABCA1 agonist in preparation of medicine for treating eye diseases
  • Application of ABCA1 agonist in preparation of medicine for treating eye diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Anterior Chamber Injection Experiment of Embodiment 1 WT Mice

[0040] WT mice were anesthetized with ketamine (100 mg / kg) and xylazine (15 mg / kg) by intraperitoneal injection. 2 μl of 100 μM GW3965 solution was slowly injected into the anterior chamber of the mouse's right eye using a Hamilton's 33-G microsyringe. The same dose of DMSO solution was injected into the fellow eye as a control. Immediately after the injection of the drug, the injection needle port was closed with erythromycin ointment. At 0, 6 and 12 hours after injection, intraocular pressure (IOP) was measured using a rebound tonometer (TonoLab, ICare, Espoo, Finland). The intraocular pressure of both eyes was measured 3 times at each time point, and the average value was calculated. At each time point, the intraocular pressure of the experimental eye and the contralateral control eye were compared, with figure 1 It showed that GW3965 100μM injected 2μl in the anterior chamber, 6 hours and 12 hours a...

Embodiment 2

[0041] Example 2 The isolated eyeball perfusion experiment of WT mice

[0042]The aqueous humor outflow rate was measured by perfusing isolated mouse eyeballs according to laboratory established methods. For construction methods, see Lei Y, Overby DR, Boussommier-Calleja A, Stamer WD, Ethier CR. Outflowphysiology of the mouse eye: pressure dependence and washout. Invest OphthalmolVis Sci. 2011;52:1865–1871. Mice were euthanized by cervical dislocation and the eyes were enucleated for perfusion. In order to detect the effect of GW3965, dissolve in DMSO with GW3965, and use 1xPBS (pH7.2-7.4) to dilute to 100 μ M solution and perfuse the eyeball for 60 minutes to exchange the aqueous humor and ensure that the concentration of the GW3965 solution is uniform throughout the experimental process. Eyeballs were then perfused at four different intraocular pressures (8, 12, 16 and 20 mmHg).

[0043] The same concentration of DMSO dissolved in PBS was used as a control, and the control...

Embodiment 3

[0046] Example 3 Western blot experiment

[0047] The porcine angle plexus cell lysates and aqueous humor outflow channel tissue lysates were prepared using RIPA solution (Biyuntian P0013B, Shanghai, China), and the protein concentration was estimated using the BCA protein concentration assay kit (Biyuntian P0010S, Shanghai, China). Equal amounts of proteins were separated by 10% SDS-PAGE (Beyontian P0670, Shanghai, China) (20 μg / lane for porcine angular plexiform cells and mouse outflow tissues, respectively). Electrophoretic transfer of the separated proteins to a nitrocellulose membrane. The membrane was blocked with 5% skim milk powder in Tris-buffered saline containing 0.05% Tween-20 (Sigma-Aldrich, Shanghai, China) at 37°C for 2 hours. Then use specific recognition ABCA1 (1:1000; Abcam, rabbit-derived ab151685, mouse-derived ab18180, Boston, USA), Cav1 (1:1000; Cell Signaling Technology rabbit-derived #3238, USA) or eNOS (1: 1000; Abcam, rabbit-derived ab66127) primary...

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PUM

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Abstract

According to the invention, an ATP-binding cassette transporter A1 (ABCA1) agonist is used for the first time; anterior chamber perfusion and in-vitro perfusion prove that the ABCA1 agonist can rapidly reduce intraocular pressure and promote aqueous humor to flow out; and in-vitro experiments show that the ABCA1 agonist acts on porcine angular plexus cells, is similar to human schlemm endothelialcells in function and participates in intraocular pressure regulation by influencing protein related to glaucoma pathogenesis. The discovery has not been reported in any literature. The ABCA1 agonistused in the invention has no cytotoxic effect; the safety of the ABCA1 agonist can be predicted, and the ABCA1 agonist can be widely applied to the preparation of medicines for treating eye related diseases.

Description

technical field [0001] The invention belongs to the field of ABCA1 agonists, and in particular relates to the application of an ABCA1 agonist in the preparation of medicines for treating eye diseases. Background technique [0002] Glaucoma is the world's first irreversible blinding eye disease. More specifically, glaucoma is a visual neuropathy (optic nerve disease), which is usually due to poor drainage of aqueous humor in the eye, resulting in increased intraocular pressure. Increased pressure in the eye damages the optic nerve and narrows the field of vision. When there is sustained high pressure in the patient, it can lead to blindness in the patient. [0003] The eye is a hollow structure containing a clear fluid called "aqueous humor". Aqueous humor is formed in the posterior chamber of the eye via the ciliary body at a rate of approximately 2.5 microliters per minute. The fluid produced at a fairly constant velocity then passes around the lens and enters the anteri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/195A61K31/18A61K9/08A61P27/06A61P27/02
CPCA61K9/0048A61K9/08A61K31/18A61K31/195A61P27/02A61P27/06
Inventor 雷苑陈宇虹孙兴怀胡春春牛亮亮秦博宋毛毛张又嘉李丽萍
Owner EYE & ENT HOSPITAL SHANGHAI MEDICAL SCHOOL FUDAN UNIV
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