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Application of cannabinoid receptor drug in preparation of drug for treating myocardial cell necrosis apoptosis

A technology of cannabinoid receptors and necroptosis, applied in the field of biomedicine, can solve the problems of less research on toxicological mechanisms

Inactive Publication Date: 2020-12-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the cardiotoxicity of quetiapine has been widely reported clinically, its toxicological mechanism is still less studied

Method used

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  • Application of cannabinoid receptor drug in preparation of drug for treating myocardial cell necrosis apoptosis
  • Application of cannabinoid receptor drug in preparation of drug for treating myocardial cell necrosis apoptosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Chronic exposure of quetiapine induces cardiotoxicity in vivo and in vitro

[0054] Antipsychotics have been widely reported clinically to prolong the QT interval and even lead to sudden cardiac death. Histopathological changes in quetiapine cardiotoxicity are still rarely reported. In our experimental study, we injected mice intraperitoneally with 60 mg / kg quetiapine (comparable to clinical therapeutic dose). After 21 days of continuous treatment, mouse hearts were harvested for histological analysis. Compared with PBS-treated control hearts, H&E staining showed that quetiapine-treated hearts showed more obvious accumulation of multifocal inflammatory cells. PicroSirius Red (PSR) staining further revealed significant accumulation of fibrous connective tissue in the perivascular and interstitial regions of quetiapine-treated hearts. The ratio of heart weight to tibial length (HW / TL) is an index reflecting myocardial interstitial edema and heart disease. Th...

Embodiment 2

[0055] Embodiment 2 Quetiapine induces cardiomyocyte necroptosis

[0056] Given that quetiapine induced mitochondrial swelling, cell membrane disintegration, and endoplasmic reticulum dilation, consistent with necrotic changes. Necroptosis is characterized by cascade activation of RIP and phosphorylation of MLKL and eventual translocation to the cell membrane leading to membrane pore formation, three common atypical antipsychotics (clozapine, olanzapine and quetiapine) treated cardiomyocytes, and detection of necroptosis activation, the results showed that any drug can increase the expression of RIP1, RIP3 and MLKL and phosphorylated MLKL (p-MLKL), especially quetiapine Ping has the strongest promoting effect on the expression of necroptosis pathway-related proteins ( figure 1 A), showing that quetiapine induces necroptosis. We then incubated myocardial HL-1 cells with different doses of quetiapine ( figure 1 B) or incubated with the same concentration of quetiapine for dif...

Embodiment 3

[0057] Example 3 Quetiapine has little effect on apoptosis and autophagy pathway

[0058] The present invention studies the effect of quetiapine on other types of cell death; cells are incubated under the same conditions as above; apoptotic markers such as caspase 3 (caspase3) and Bcl-2 are treated with different quetiapine The conversion of LC3B-I to LC3B-II is a sign of autophagy activation. The present invention observed that the level of LC3B-II increased very slightly under different doses of quetiapine or different treatment times. In all different treatments, Beclin 1 did not change significantly.

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Abstract

The invention belongs to the field of biological medicines, and relates to a new application of a cannabinoid receptor drug, in particular to an application of a cannabinoid receptor type 1 (CB1R) antagonist and a cannabinoid receptor type 2 (CB2R) agonist in preparation of a drug for treating myocardial cell necrotic apoptosis. The invention also provides a corresponding kit. Quetiapine is a common atypical antipsychotic and is used for treating schizophrenia, bipolar affective disorder, severe depression and other mental disorders. Experiments prove that quetiapine promotes inflammatory infiltration and fibrosis reconstruction of myocardial cells; quetiapine has the effect of promoting RIP3 and MLKL and activates a myocardial cell necrotic apoptosis pathway, and the cannabinoid receptortype 1 (CB1R) antagonist and the cannabinoid receptor type 2 (CB2R) agonist can significantly inhibit the necrotic apoptosis pathway, so the cannabinoid receptor type 1 (CB1R) antagonist and the cannabinoid receptor type 2 (CB2R) agonist are used for treating quetiapine cardiotoxicity. The invention provides a novel application of the cannabinoid receptor type 1 (CB1R) antagonist and the cannabinoid receptor type 2 (CB2R) agonist, and provides novel reference data for development of myocardial cytotoxicity treatment drugs.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to necroptosis regulating drugs, in particular to new uses of cannabinoid receptor drugs, especially to type 1 cannabinoid receptor (CB1R) antagonists and type 2 cannabinoid receptor (CB2R) agonists The application of agents in cardiomyocyte necroptosis agents. Background technique [0002] Atypical antipsychotics, including clozapine, olanzapine, and quetiapine, are commonly used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder. Quetiapine, which is chemically similar to clozapine and olanzapine, was approved in 1997 on the basis of clinical trials in patients with schizophrenia. More than 22 million people worldwide are prescribed quetiapine, the most prescribed atypical antipsychotic in the United States, according to Astra Zeneca. Quetiapine is effective in the acute and maintenance treatment of major depressive disorder ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P9/00
CPCA61K45/00A61P9/00
Inventor 李立亮李小青姜宴彭钊刘晓晨
Owner FUDAN UNIV
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