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Antagonist composition and application thereof in preparation of medicine for treating sleep disorder and mental disease

A technology for mental diseases and sleep disorders, applied in the field of biomedicine, can solve the problems of uncontrollable side effects, inability to act locally, and unknown scope of action, and achieve the effect of improving sleep disorders.

Pending Publication Date: 2022-03-25
SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many antidepressants are accompanied by the effect of inhibiting REM sleep and improving depressive symptoms. These drugs reflect the high correlation between the regulation of REM sleep and the improvement of depressive symptoms, but most of the targets of antidepressants in the brain are not Unclear, especially the regulation mechanism of sleep
Antidepressant medications cannot be targeted due to poor understanding of how depression occurs
Moreover, because the mechanism of action is unclear, it cannot act on the local area. Because of its target, the range of action is unknown, so the side effects are uncontrollable and more likely to cause side effects
At present, there is no good treatment method for the co-morbidity of sleep and mental illness in the prior art

Method used

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  • Antagonist composition and application thereof in preparation of medicine for treating sleep disorder and mental disease
  • Antagonist composition and application thereof in preparation of medicine for treating sleep disorder and mental disease
  • Antagonist composition and application thereof in preparation of medicine for treating sleep disorder and mental disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Exploring the regulatory role of CRH neurons in the subthalamic nucleus on REM sleep and fear responses

[0067] This example explores the regulatory effect of CRH neurons in the subthalamic nucleus on REM sleep and fear response.

[0068] Firstly, AAV9-Crh-Cre and AAV9-DIO-Syn-hM4Di-mCherry (experimental group) were expressed in the subthalamic nucleus of the subject (C57BL6J wild-type mice) through stereotaxic brain region and micro-injection of virus (experimental group). A total of 75 nanoliters were injected after mixing the substance ratio of 1:1); or AAV9-Crh-Cre and AAV9-DIO-Syn-mCherry (control group) (after mixing the two at a substance ratio of 1:1 A total of 75 nL was injected). Wherein AAV9-Crh-cre is used to express the Cre enzyme in the neurons expressing CRH in the subject, wherein the CRH promoter sequence was reported by J Chen et al. in 2012 (see for details figure 1 ). The sequence of AAV9-DIO-Syn-hM4Di-mCherry and AAV9-DIO-Syn-mCherry contains a ...

Embodiment 2

[0073] Exploring the overlap between CRH neurons and glutamatergic neurons in the subthalamic nucleus

[0074] After the present invention confirms the regulating effect of the CRH neurons of the subthalamic nucleus on REM sleep and fear response through Example 1, the CRH neuron types of the subthalamic nucleus are further analyzed. This example explores the overlap between CRH neurons and glutamatergic neurons in the subthalamic nucleus.

[0075] By injecting AAV-DIO-EYFP virus (injection 75 nanoliters) into the subthalamic nucleus ( Figure 3A ), to infect glutamatergic neurons in the subthalamic nucleus, and it was observed that the subthalamic nucleus expresses a large number of glutamatergic neurons. In situ hybridization staining was used to judge whether the expression of endogenous glutamic acid RNA was co-labeled with the viral expression EYFP to verify the specificity of the VGLUT2-cre mice used. Statistical results such as Figure 3B As shown, it can be seen tha...

Embodiment 3

[0081] Exploring the effects of CRH receptor antagonists on sleep and fear response

[0082] This example explores the effects of administering CRH receptor antagonists on sleep and fear responses.

[0083] The CRH antagonist group was used as the experimental group, and the DMSO solvent group was used as the control group. The CRH antagonist is selected from CP154526, which can bind to CRH receptor type 1, thereby competitively blocking the binding of CRH transmitters. Inject 75 nanoliters of a mixture of AAV-DIO-EF1a-ChR2-mCherry and AAV-Crh-cre (mass ratio 1:1) in the subthalamic nucleus of the subject (C57BL6J wild-type mice) The ChR2 light-activated protein was expressed in the CRH neurons, and after 4 weeks of virus expression, an optical fiber was implanted in the subthalamic nucleus to deliver blue light, so that the blue light stimulated the ChR2 protein to activate the CRH neurons in the subthalamic nucleus, and administered the protein to the lateral globus pallidu...

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Abstract

The invention provides an antagonist composition and application of the antagonist composition in preparation of a medicine for treating sleep disorder and mental disease. The antagonist composition comprises a CRH receptor antagonist and a glutamic acid energy receptor antagonist. The invention firstly discovers that the sleep duration / stability and fear reaction degree of REM can be changed by regulating and controlling the activity of neurons of corticotropin releasing hormone of the subthalamic nucleus or neurons of a globular pallidum area on the outer side of the downstream of the subthalamic nucleus, which indicates that the subthalamic nucleus and the cerebral area of the downstream of the subthalamic nucleus are functional regulation and control targets for coincidence of sleep disorder and dysfear-related mental diseases. The invention also finds that the subthalamic nucleus CRH neuron and the glutamic acid energy neuron have a very high coincidence ratio for the first time. Based on the above findings, the present invention combines a CRH receptor antagonist with a glutamic acid receptor antagonist to regulate CRH and glutamic acid signal transmission of subthalamic nucleus-lateral globular pallidum, thereby improving sleep disorders and mental disorder comorbidity associated with fear mood disorder.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and relates to an antagonist composition and its application in the preparation of medicines for treating sleep disorders and mental diseases. Background technique [0002] There is a high comorbidity rate between sleep disorders and mental illnesses. David Nutt et al. reported in 2008 that more than 83% of patients with depression had sleep disorders, and Luc Staner reported 51%-78% of patients with anxiety disorders in 2003. Sleep disturbance is present. This reflects the high correlation between sleep and the development of mental illness. Sleep includes non-rapid eye movement sleep (NREM) and rapid eye movement sleep (rapid eye movement sleep, REM), each with different functions. Changes in REM sleep structure are more common in patients with mental disorders associated with fear disorders such as depression, anxiety and post-traumatic stress disorder. For example, Dieter Riemann et al....

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/505A61K31/53A61K31/519A61P25/20A61P25/24A61P25/22A61P25/00
CPCA61K45/06A61K31/505A61K31/53A61K31/519A61P25/20A61P25/24A61P25/22A61P25/00
Inventor 王立平曾渝婷赵炳皓
Owner SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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