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Application of cannabinoid receptor type 1 (CB1R) antagonist in preparation of drug for treating pyroptosis of cardiac muscle cells

A technology of cannabinoid receptors and cardiomyocytes, applied in the field of biomedicine, can solve problems such as few studies

Inactive Publication Date: 2021-05-07
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, most of the studies on myocardial damage caused by psychotropic drugs focus on case reports or retrospective analysis, and there are few in-depth studies on its mechanism

Method used

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  • Application of cannabinoid receptor type 1 (CB1R) antagonist in preparation of drug for treating pyroptosis of cardiac muscle cells
  • Application of cannabinoid receptor type 1 (CB1R) antagonist in preparation of drug for treating pyroptosis of cardiac muscle cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Olanzapine mediates cardiotoxicity by inducing cardiomyocyte pyroptosis

[0048] Based on previous studies, it has been found that antipsychotics have significant cardiotoxicity during long-term chronic use, and olanzapine, as a new generation of atypical antipsychotics, is also widely used due to its possible serious cardiotoxicity. It is used cautiously in clinical practice due to side effects, and the related pathways of olanzapine cardiotoxicity are rarely reported; in this experiment, 2.5mg / kg olanzapine (equivalent to the clinical therapeutic dose) was intraperitoneally injected into mice. After 21 days of continuous treatment, mouse heart tissue was collected and its RNA was extracted. Then it was reverse transcribed into cDNA for transcriptomic analysis. Significant enrichment of the pyroptotic pathway was found in the genes of the olanzapine-treated mice compared with the PBS-treated control group ( figure 1 A). It suggested that under the chronic ...

Embodiment 2

[0049] Example 2 Identification of CB1R as a Novel Regulator of Cardiomyocyte Pyroptosis

[0050] Based on the cross-analysis of transcriptomics and proteomics, it was found that olanzapine can significantly activate multiple pathways when it causes myocardial toxicity, including the endogenous cannabinoid system, endocytosis, PI3K / Akt pathway, etc. The present invention adopts different pathways specific inhibitors, and compared and analyzed the effects of each inhibitor on the protein expression of pyroptotic molecules NLRP3, Caspase-1 and GSDMD in cardiomyocytes. After statistical analysis, it was found that after inhibiting the function of the endogenous cannabinoid system, the pyroptosis was maximized. Inhibition to a certain extent suggests that the endogenous cannabinoid system is an important link in the regulation of cardiomyocyte pyroptosis; therefore, the present invention continues to use CB1R, an important component of the endogenous cannabinoid system, as the rese...

Embodiment 3

[0052] Example 3 Inhibition of CB1R can effectively relieve olanzapine cardiotoxicity

[0053] The mice were continuously intraperitoneally injected with 2.5 mg / kg olanzapine (equivalent to clinical therapeutic dose) for 21 days, and the mice were pretreated with CB1R-specific inhibitor AM281 or Rimonabant within half an hour before the daily injection of olanzapine. The mice in the positive control group were only treated with olanzapine. After 21 days, the heart tissue of the mice was collected for histological analysis, and the heart weight, body weight and tibia length of the mice were measured. Compared with the control group, H&E staining and PicroSiriusRed (PSR) staining showed that olanzapine-treated hearts showed a large number of inflammatory cell aggregation and obvious accumulation of myocardial interstitial fibrous connective tissue ( figure 2 C), quantitative analysis of fibrous connective tissue staining showed that the area of ​​fibrous connective tissue in ol...

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Abstract

The invention belongs to the field of biological medicine, and relates to a novel application of a cannabinoid receptor type 1 (CB1R) antagonist, in particular to identification of a novel cardiac muscle pyroptosis regulatory factor CB1R and application of a CB1R selective antagonist in preparation of a drug for treating and resisting psychotropic drug myocardial cytotoxicity. The invention also provides a corresponding kit. Experiments prove that olanzapine promotes myocardial cell inflammatory infiltration and fibrosis reconstitution, olanzapine has the effects of promoting NLRP3 inflammatory small body formation and activating a myocardial cell pyroptosis pathway to cause cardiotoxicity, CB1R is an important regulatory factor of myocardial cell pyroptosis, and the CB1R selective antagonist can be used for treating olanzapine cardiotoxicity. A new clue for development of myocardial cytotoxicity treatment drugs is opened up.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to the identification of pyroptosis regulatory factors and their new application in medicine. It specifically relates to the application of type 1 cannabinoid receptor (CB1R) antagonists in the preparation of medicaments for the treatment of cardiomyocyte pyroptosis, especially the identification method of type 1 cannabinoid receptor (CB1R) regulating pyroptosis and type 1 cannabinoid receptor antagonism Therapeutic use of antipsychotics in cardiotoxicity. Background technique [0002] The prior art discloses that atypical antipsychotics, including olanzapine, clozapine, and quetiapine, are among the most effective therapeutic agents in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder. an important class of drugs. However, with the continuous application and popularization of antipsychotic drugs, the accompanying toxic and side e...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P9/00
CPCA61K45/00A61P9/00
Inventor 李立亮李小青林馨怡王婧
Owner FUDAN UNIV
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