Application of MST4 related substances in preparation of medicine for treating neuroinflammation reaction after cerebral hemorrhage

A related substance, MST4 technology, applied in the direction of drug combination, neurological diseases, pharmaceutical formulations, etc., to achieve the effect of alleviating neurological deficits

Pending Publication Date: 2021-11-02
THE FIRST AFFILIATED HOSPITAL OF WANNAN MEDICAL COLLEGE YIJISHAN HOSPITAL OF WANNAN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no report on whether MST4 is i

Method used

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  • Application of MST4 related substances in preparation of medicine for treating neuroinflammation reaction after cerebral hemorrhage
  • Application of MST4 related substances in preparation of medicine for treating neuroinflammation reaction after cerebral hemorrhage
  • Application of MST4 related substances in preparation of medicine for treating neuroinflammation reaction after cerebral hemorrhage

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1, experimental design

[0050] 1. Experimental design: such as figure 1 As shown, mice were assigned to four independent experiments and all design details are listed.

[0051] Experiment 1: 30 mice were divided into sham operation group and 6h, 12h, 24h and 72h groups after cerebral hemorrhage. The levels of MST4 and NLRP3 were detected by western blot. Brain tissue was taken for immunofluorescence (IF) detection.

[0052] Experiment 2: Randomly divided into sham operation group, ICH group, ICH+control AAV group, ICH+MST4 AAV group, 60 each. Western blot detection of MST4, NLRP3, IL-1β, caspase-1 and TNF-α protein levels (n=6), brain tissue IF (n=3), neurological function test 24h after cerebral hemorrhage (n=15) and brain water content (n=6).

[0053] Experiment 3: 30 rats in each of the ICH group and the ICH+Hesperidin group. All mice were sacrificed 24 hours after cerebral hemorrhage, and western blot (n=6), BWC (n=6), neurological examination (n=1...

Embodiment 2

[0067] Example 2. Expression of MST4 and NLRP3 and their cellular localization after ICH

[0068] MST4 protein levels were significantly increased at 12 and 24 hours after ICH and peaked at 12 hours (*p figure 2 A, B). Elevated NLRP3 protein levels were observed at 12 and 24 hours after ICH, peaking at 24 hours (*p figure 2 A, C). Both MST4 and NLRP3 levels decreased with the peak. 24 hours after ICH was chosen as the observation time point for experiments 2, 3 and 4. Immunofluorescence of MST4 or NLRP3 with Iba1 was performed. Both MST4 and NLRP3 were expressed in microglia and increased after ICH ( figure 2 D).

Embodiment 3

[0069] Example 3, MST4 AAV inhibits the activation of NLRP3 inflammasome

[0070] The expressions of MST4, NLRP3 inflammasome components, IL-1β, and TNF-α increased after ICH (*p image 3 A-F). MST4 AAV attenuated caspase-1 activation, IL-1β and TNF-α secretion (#p image 3 A-F). MST4 AAV administration significantly improved neurological deficits (*p image 3 G-H). Consistent with neurological assessment, BWC was elevated in the ipsilateral hemisphere after ICH whereas MST4 AAV died BWC (*p image 3 I).

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Abstract

The invention discloses an application of an MST4 related substance as the following (a) and/or (b) and/or (c) and/or (d) and/or (e) and/or (f) and/or (g): (a) preparing a substance for promoting expression of MST4 and NLRP3; (b) preparing a substance for inhibiting MST4 expression; (c) preparing a substance for inhibiting the expression of NLRP3; (d) preparing a substance for inhibiting the expression of MST4 and promoting the expression of NLRP3; (e) preparing a substance for inhibiting release of IL-1beta and TNF-alpha; (f) preparing substances for preventing and/or treating neurological impairment and encephaledema; and (g) preparing a substance for preventing and/or treating neuroinflammation reaction after cerebral hemorrhage. The test proves that the MCC950 inhibits the interaction of the MST4 and the NLRP3 to inhibit the neuroinflammatory reaction after cerebral hemorrhage; compared with a sham group, the expression of endogenous MST4 and NLRP3 after ICH is increased, and MST4 and NLRP3 are co-localized in microglial cells respectively; the MCC950 obviously alleviates neurological impairment and encephaledema, and has no influence on the expression of MST4 protein.

Description

technical field [0001] The invention relates to the application of MST4-related substances in the preparation of medicines for treating neuroinflammation after cerebral hemorrhage. Background technique [0002] Intracerebral hemorrhage (ICH) is a serious stroke that occurs in 10%-15% of cases and is accompanied by severe neurological deficit. The primary brain injury was caused by a hematoma after ICH. The inflammatory cascade accelerates the hematoma and leads to cell death. Microglia are rapidly activated after ICH, and then release proinflammatory cytokines and chemokines to cause secondary brain injury. Accumulating evidence indicates that neuroinflammation plays a crucial role in the pathophysiology of secondary brain injury after ICH. [0003] Mammalian serine / threonine protein kinase 4 (mammalian Ste20-like kinase 4) MST4 is a negative regulator of inflammation. MST4 is classified as a member of the GCK subfamily, belongs to MST kinase, and is abundantly expressed ...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/64A61K31/454A61P25/00
CPCA61K45/00A61K31/64A61K31/454A61P25/00
Inventor 徐阳吴晓东黄四妹胡文杰储照虎赵守财马领松
Owner THE FIRST AFFILIATED HOSPITAL OF WANNAN MEDICAL COLLEGE YIJISHAN HOSPITAL OF WANNAN MEDICAL COLLEGE
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