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Application of coptisine serving as indoleamine 2, 3-dioxygenase (IDO)inhibitor

A technology of dioxygenase and coptisine, applied in the field of medicine, can solve problems such as unreported, and achieve the effect of good potential of research and development of new drugs

Inactive Publication Date: 2012-07-18
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, the purposes of coptisine in the preparation of IDO inhibitors and its role in the treatment of Alzheimer's disease as IDO inhibitors have not been reported.

Method used

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  • Application of coptisine serving as indoleamine 2, 3-dioxygenase (IDO)inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] 1. Preliminary detection of IDO inhibitory activity

[0022] 19(1): 22-9)。 The construction of the plasmid containing the human IDO gene, expression in E. coli, extraction and purification were carried out according to the method reported by Littlejohn et al. (Protein Exp Purif, 2000. 19(1): 22-9). The inhibitory activity of compounds against IDO was tested as described. Mix 50 mM potassium phosphate buffer (pH 6.5), 40 mM vitamin C, 400 μg / ml catalase, 20 μM methylene blue, substrate L-tryptophan and the sample to be tested, and incubate the mixture at 37 °C for 5 minutes , then IDO enzyme was added to the above mixture, the reaction was carried out at 37 °C for 30 minutes, 200 μl of 30% (w / v) trichloroacetic acid was added to terminate the reaction, and the reaction system was heated at 65 °C for 15 minutes to complete the reaction. Conversion of formylkynurenine to kynurenine, followed by centrifugation at 12,000 rpm for 10 minutes, the supernatant was mixed with an...

Embodiment 2

[0037] Example 2: Response to β-amyloid (Aβ 1-42 ) and γ-interferon (IFN-γ) combined-induced neuronal cell injury and protection against apoptosis

[0038] 1. Method

[0039] 1.1. Cell Lines and Cell Culture

[0040] The rat neuronal cell line PC12 was used. PC12 cells were cultured in DMEM medium with 10% inactivated fetal bovine serum, 50U / ml penicillin, and 25μg / ml streptomycin. Cells were placed at 37 °C with 5 % CO 2 In the incubator, passage 1:4 when 80%-90% confluent.

[0041] 1.2. Establishment of Alzheimer's disease (AD) cell model

[0042] When PC12 cells grow to 60% confluence in a 6-well plate, add 1 ml of 25 μM Aβ 1-42 DMEM medium for 24 h. Then change to 1ml of 1×10 3 The AD neuron model was established after the DMEM medium of U / mL IFN-γ was cultured for 24 h.

[0043] 1.3. Grouping

[0044] The cells in this experiment were divided into 5 groups, namely blank group, Aβ group, Aβ+IFN-γ group, coptisine group, and 1-MT positive control group. Blank gro...

Embodiment 3

[0067] Example 3: Influence on the learning and memory ability of Alzheimer's rats

[0068] 1. Experimental method:

[0069] 1.1 Main reagents and instruments

[0070] L-kynurenine (L-kynurenine, L-KYN), L-tryptophan (L-Tryptophan, L-TRP) standards were purchased from sigma, the product numbers are K8625, T8941, respectively. Morris Water Maze: Shanghai Shift Information Technology Co., Ltd. High performance liquid chromatograph: Shimadzu LC-10A, Japan.

[0071] 1. 2. Experimental animals

[0072] APP-PS1 Alzheimer's disease mice (AD mice), 40 males and 12 wild-type B6C3 mice (WT mice), weighing 35±5 g, were purchased from Nanjing Animal Research Institute. APP-PS1 double-transgenic mice can express the fusion of mutant human presenilin (DeltaE9) and human-mouse amyloid preprotein (APPswe), and can reproduce and survive normally. Usually there are more senile plaques in the brain after 30 weeks of age, showing symptoms of dementia, and it is used as a model organism for A...

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Abstract

The invention belongs to the field of medicine and particularly relates to an application of coptisine serving as an indoleamine 2, 3-dioxygenase (IDO) inhibitor. The coptisine is an IDO reversible inhibitor, the inhibitor constant Ki is 5.76mu M, the half effective inhibition concentration (IC50) in vitro and at a cell level is 6.31mu M and 7.11mu M respectively, and the inhibition effect is obviously better than that of existing inhibitor of 1-methyl trytophan. According to the application of the coptisine serving as the indoleamine 2, 3-dioxygenase inhibitor, the coptisine is used as the IDO inhibitor so that IDO activity which rises abnormally in a neuron cell model and an animal model in alzheimer disease is effectively lowered, functions of curing alzheimer disease are achieved, and the functions include a protective function to neuron cells, an anti-apoptosis function and a function of improving learning and memory capabilities of animals having alzheimer disease. The coptisine and hydrochloride of the coptisine are used as an IDO inhibitor so that the application prospect is wide, and the coptisine and the hydrochloride of the coptisine can be used for curing serious diseases with pathological characteristics of IDO mediates and trytophan metabolic pathways such as alzheimer disease, depressive disorders, cancers, acquired immune deficiency syndrome, cataract and the like.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the use of coptisine as an inhibitor of indoleamine 2, 3-dioxygenase (IDO). Background technique [0002] The prior art discloses that indoleamine 2, 3-dioxygenase (Indoleamine 2, 3-dioxygenase, IDO) is an enzyme containing heme in cells, and is the only enzyme that can catalyze the metabolism of tryptophan outside the liver. It is the rate-limiting enzyme that decomposes along the kynurenine pathway to a series of metabolites including quinolinic acid (MacKenzie, C. R. et. al. Current Drug Metabolism , 2007, 8: 237-244). [0003] IDO is related to many physiological and pathological processes. Studies on pregnant mouse models have found that syncytiotrophoblast cells and antigen-presenting cells at the maternal-fetal interface can synthesize IDO, and the dynamic changes in IDO expression are consistent with embryogenesis. If the effect of IDO is specifically blocked, it can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4375A61P25/28A61P25/24A61P35/00
Inventor 杨青于丹何晓婕杨双双
Owner FUDAN UNIV
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