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DRD1 protein and application of agonists of DRD1 protein in preparation of medicine for treating related inflammatory diseases of NLRP3 inflammasome

A technology for inflammatory diseases and inflammasomes, applied in the field of DRD1 protein and its agonists, which can solve problems such as no successful examples of inflammatory diseases

Active Publication Date: 2015-01-07
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current basic and clinical research in this field is mainly focused on the use of dopamine and dopamine receptor agonists to treat and relieve Parkinson's disease, and there is no successful example for the treatment of NLRP3 inflammasome-related inflammatory diseases

Method used

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  • DRD1 protein and application of agonists of DRD1 protein in preparation of medicine for treating related inflammatory diseases of NLRP3 inflammasome
  • DRD1 protein and application of agonists of DRD1 protein in preparation of medicine for treating related inflammatory diseases of NLRP3 inflammasome
  • DRD1 protein and application of agonists of DRD1 protein in preparation of medicine for treating related inflammatory diseases of NLRP3 inflammasome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1, DA and its agonists inhibit the activation of macrophage NLRP3 inflammasome in vitro

[0057] 1. DA inhibits the secretion of IL-1β

[0058] 1. On the first day, divide BMDM onto a twelve-well plate, 5*10 per well 5 cells.

[0059] 2. On the second day, the supernatant was first aspirated, and 500 μl of opti-MEM containing ultra-LPS (500 ng / ml) was added to each well for three hours. Divided into five groups with three replicate wells in each group.

[0060] The first group, the negative control group.

[0061] In the second group, Nigericin with a final concentration of 10 μM was added to each well for half an hour.

[0062] In the third group, DA with a final concentration of 0.15 mM was added to each well for three hours, and Nigericin with a final concentration of 10 μM was added for half an hour.

[0063] In the fourth group, DA with a final concentration of 0.2 mM was added to each well for three hours, and Nigericin with a final concentration of 1...

Embodiment 2

[0144] Example 2, DRD1 protein can inhibit central system inflammation

[0145] 1. DA can inhibit the activation of microglial inflammasome through DRD1

[0146] 1. On the first day, divide the microglial cells of wild mice (WT) and Drd1-deficient mice into twelve-well plates, 1*10 per well 6 cells.

[0147] 2. On the second day, the supernatant was first aspirated, and 500 μl of opti-MEM containing ultra-LPS (500 ng / ml) was added to each well for three hours. Each of the two types of microglia was divided into three groups, a total of six groups, and each group had three replicate wells.

[0148] The first group, WT mouse microglia, negative control group.

[0149] In the second group, WT mouse microglial cells, Nigericin with a final concentration of 10 μM was added to each well for half an hour.

[0150] In the third group, WT mouse microglial cells, DA with a final concentration of 0.2 mM was added to each well for three hours, and Nigericin with a final concentration ...

Embodiment 3

[0184] Example 3, DRD1 protein can inhibit peripheral system inflammation

[0185] 1. DA can inhibit LPS-induced peripheral inflammation

[0186] 1. Select 8-12 week old wild mice (WT), and divide them into three groups with three mice in each group.

[0187] 2. The first group, wild-type mice, was intraperitoneally injected with PBS as a negative control

[0188] The second group, wild-type mice, intraperitoneally injected with LPS, the injection dose was 20mg / kg

[0189] The third group, wild-type mice, were injected intraperitoneally with LPS and DA at the same time, wherein the injection dose of LPS was 20 mg / kg, and the injection dose of DA was 50 mg / kg

[0190] 3. After four hours, collect the blood by pulling out the eyeball, let it stand at room temperature for half an hour, then centrifuge at low speed for half an hour, and collect the serum.

[0191] 4. The serum obtained in step 3 is used for the determination of cytokines such as IL-1β and IL-18 by ELISA method....

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Abstract

The invention discloses DRD1 protein and an application of agonists of DRD1 protein in preparation of medicine for treating related inflammatory diseases of NLRP3 inflammasome. Under the action of endogenous agonist dopamine, the protein induces degradation of NLRP3 protein which is an important component of inflammasome and has the function of inhibiting maturity and secretion of inflammatory factors such as IL-1 beta and the like, so that activation of NLRP3 inflammasome is inhibited. According to the invention, the application of the DRD1 protein serving as a target point of related inflammatory diseases, such as peripheral nervous system inflammation and central nervous system inflammation, of NLRP3 inflammasome is provided, and the DRD1 protein can be used for screening and developing medicine for the related inflammatory diseases of NLRP3 inflammasome; and the artificially synthesized agonists A-68930, (+ / -)-SKF-38393hydrocholride, SKF89626 and 6-Chloro-PB hydrobromide of the DRD1 protein are further provided and have anti-inflammatory functions, and original ideas and theoretical support are provided for preparation of anti-inflammatory medicine and treatment of the inflammatory diseases by the agonists and active ingredients of the agonists.

Description

technical field [0001] The invention relates to the use of DRD1 protein and its agonist in the preparation of medicines for treating inflammatory diseases related to NLRP3 inflammasomes. Background technique [0002] The NLRP3 inflammasome is an intracellular polyprotein complex, which is mainly composed of NLRP3 (NACHT, LRR and PYD domains-containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD) and caspase-1 Composed of three proteins. The NLRP3 inflammasome and its signaling pathway play a crucial role in initiating inflammation and related immune responses (Davis et al., 2011, Annu Rev Immunol; Marltinon et al., 2009, Immunol). Therefore, the activation of NLRP3 inflammasome must be precisely and strictly regulated. If the inflammatory response is disordered, such as excessive amplification or persistence, it will cause damage to the body and even lead to the occurrence of inflammatory diseases. The abnormal activation of NLRP3 inflammaso...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/353A61K31/55A61P3/10A61P9/10A61P19/06A61P1/00A61P1/16A61P11/00A61P35/00A61P25/28A61P29/00
Inventor 周荣斌江维闫宜青
Owner UNIV OF SCI & TECH OF CHINA
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