Application of hexokinase 2-specific inhibitor in acute central nervous system injury diseases

A technology of hexokinase and central nervous system, applied in the field of biomedicine, can solve the problems of not benefiting stroke patients and unsatisfactory results

Inactive Publication Date: 2017-06-20
GUANGZHOU CELLPROTEK PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the results of current clinical trials of drugs targeting this mechanism are not satisfactory
For example: Fingolimod (Fingolimod) and Natalizumab (Natalizumab), which target the inflammatory response of the peripheral immune system, although they can effectively inhibit the infiltration of lymphocytes into the brain parenchyma, the results of clinical trials have shown that receiving treatment does not make Stroke Patient Group Benefits

Method used

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  • Application of hexokinase 2-specific inhibitor in acute central nervous system injury diseases
  • Application of hexokinase 2-specific inhibitor in acute central nervous system injury diseases
  • Application of hexokinase 2-specific inhibitor in acute central nervous system injury diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1 The enhancement of glycolysis pathway caused by hypoxia is necessary for the activation of microglia

[0032] Materials: mouse BV2 microglial cell line, high glucose DMEM medium (Gibco, 11965-118), fetal bovine serum (Gibco, 10099-141), 2-deoxyglucose (Sigma-Aldrich, D8375), 2-( N-7-nitro-2,1,3-benzodiazol-4-amino)-2-deoxyglucose (2-NBDG, Thermo Fisher Scientific, N13195), Annexin / PI staining kit (Biotool, B32115) , flow cytometer (CytoFLEX S), laser confocal microscope (Nikon A1 Spectral Confocal Microscope), hypoxia workstation (Coy LABORATORY PRODUCTS).

[0033] Antibody information for Western blotting and immunofluorescence:

[0034] CD 11b antibody (Novus biologicals, NB 110-89474);

[0035] TNF-α antibody (CST, 11498);

[0036] IL-1β antibody (CST, 12507);

[0037] IL-6 antibody (Bioss, bs-6309R);

[0038] Antibody to α-Tubulin (Bioworld, AP0064).

[0039] method:

[0040] a) Cell culture: the mouse microglial cell line BV2 was grown in high-glucos...

Embodiment 2

[0049] Example 2 Hypoxia-induced activation of microglial cells involves up-regulated expression of hexokinase family members

[0050] Materials: mouse BV2 microglial cell line, primary cultured mouse microglial cells, high glucose DMEM medium (Gibco, 11965-118), fetal bovine serum (Gibco, 10099-141), RNA extraction reagent TRIzol ( Thermo Fisher Scientific, 15596-018), RNA Quantification Kit (Thermo Fisher Scientific, Q10211), SuperReal qPCR PreMix (SYBR Green) (Tiangen, FP202-01), real-time fluorescent quantitative PCR instrument (Applied Biosystems), hypoxia workstation (Coy LABORATORY PRODUCTS).

[0051] Antibody information for Western blotting:

[0052] Hexokinase 1 antibody (Abcam, 150423);

[0053] Hexokinase 2 antibody (CST, 2867s);

[0054] Hexokinase 3 antibody (Santa Cruz, sc-28890);

[0055] Antibody to α-Tubulin (Bioworld, AP0064).

[0056] The primer information used in real-time fluorescent quantitative PCR is as follows:

[0057] Mouse HK1 forward primer...

Embodiment 3

[0081] Example 3 Hexokinase 2, but not other hexokinase family members, mediates hypoxia-induced activation of microglia

[0082] (1) Hexokinase 2 interference can effectively inhibit the activation process of microglia induced by hypoxia

[0083] Materials: mouse BV2 microglial cell line, primary cultured mouse microglial cells, high glucose DMEM medium (Gibco, 11965-118), fetal bovine serum (Gibco, 10099-141), siRNA fragments, siRNA transfection Staining reagent (LipofectamineRNAiMAX Reagent, Thermo Fisher Scientific, 13778-500), inverted phase contrast microscope (NikonECLIPSE Ti Microscope), laser confocal microscope (Nikon A1 Spectral Confocal Microscope), hypoxia workstation (Coy LABORATORY PRODUCTS).

[0084] Antibody information for Western blotting:

[0085] Hexokinase 1 antibody (Abcam, 150423);

[0086] Hexokinase 2 antibody (CST, 2867s);

[0087] Hexokinase 3 antibody (Santa Cruz, sc-28890);

[0088] CD 11b antibody (Novus biologicals, NB 110-89474);

[0089] An...

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Abstract

The invention belongs to the field of biomedicines, and relates to an application of a hexokinase 2-specific inhibitor in the prevention and treatment of acute central nervous system injury diseases. The invention discovers for the first time that both the hexokinase 2-specific inhibitor and selective gene knockdown of hexokinase 2 can effectively reduce cerebral injuries caused by cerebral arterial embolisms in rats by inhibiting microglial cell-mediated neuroinflammation, indicating that various medicines for selectively inhibiting hexokinase 2 have a nerve protection effect.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to the application of specific inhibitors of hexokinase 2 and the like in the prevention and treatment of acute central nervous system injury diseases. Background technique [0002] Cerebral stroke, also known as cerebral apoplexy, is an acute cerebrovascular disease. It is a disease that causes brain tissue damage due to sudden rupture of blood vessels in the brain or reduction of cerebral blood flow due to blood vessel blockage, including ischemic and hemorrhagic strokes. , of which ischemic stroke accounts for about 85% of the total cases. [0003] Tissue plasminogen activator (t-PA) is currently an FDA-approved anti-stroke drug. However, t-PA is only applicable within 3-6 hours after stroke, and patients also have the risk of cerebral hemorrhage and cerebral edema after receiving treatment. These defects make the application of t-PA very limited, and there are very few patients who ben...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/416A61P25/28A61P9/10
CPCA61K45/00A61K31/416A61K31/7004A61K31/19A61K31/506A61K31/7105A61K2300/00C07K16/40A61K45/06A61P25/00A61K2039/505C12N15/1137
Inventor 李媛银巍卢秉政盛龙祥陈文礼苏兴文孙虹嘉琪陈玉嫔薛冬冬颜光美
Owner GUANGZHOU CELLPROTEK PHARMA
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