Application of lovastatin to preparing microglial cell activation inhibitors

A technology of microglia and lovastatin, which is applied in the field of medicine, can solve the problems of scarcity of small molecules with blood-brain barrier permeability, hinder the development of microglia regulators for the treatment of neuropathic diseases, etc. Effects of neuropathic pain and good blood-brain barrier permeability

Inactive Publication Date: 2019-07-26
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Since the 1990s, small-molecule modulators targeting TLR4 and its accessory protein myeloid differentiation factor 2 (MD2) have been extensively studied, and many small-molecule modulators of TLR4 have been published; Capable small molecules are very rare, and none of the TLR4 small molecule modulators has passed phase III clinical trials
This has largely hampered the development of microglial modulators and potential therapeutics for neuropathic diseases

Method used

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  • Application of lovastatin to preparing microglial cell activation inhibitors
  • Application of lovastatin to preparing microglial cell activation inhibitors
  • Application of lovastatin to preparing microglial cell activation inhibitors

Examples

Experimental program
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Effect test

Embodiment 1

[0071] (1) BV-2 microglia were cultured in an incubator at 37°C (containing 5% carbon dioxide). Medium: DMEM+10% FBS; when the cell density reaches 90% full plate rate, passage. BV-2 microglia were resuspended in culture medium (cell density: 2 × 10 5 cells / ml) and plated in 96-well plates overnight. The medium was replaced with DMEM without FBS, 200 ng / ml LPS and different concentrations of the inhibitor to be tested (formula (I)) were added, and RNA was extracted 24 hours later. The mRNA expressions of IL-6, COX-2 and TNF-α were detected by qPCR instrument (Analytik Jena, Thuringia, Germany).

[0072] Example 1 of the present invention characterizes the inhibitory activity of lovastatin. The result is as figure 1 , figure 2 and image 3 shown, where figure 1 This is the inhibitory effect of lovastatin on the mRNA expression of inflammatory factor IL-6 in BV-2 microglia in Example 1 of the present invention; figure 2 This is the inhibitory effect of lovastatin on th...

Embodiment 2

[0075] (2) BV-2 microglia were cultured in an incubator at 37°C (containing 5% carbon dioxide). Medium: DMEM+10% FBS; when the cell density reaches 90% full plate rate, passage. BV-2 microglia were resuspended in culture medium (cell density: 2 × 10 5 cells / ml) and plated in 96-well plates overnight. The medium was replaced with DMEM without FBS, 200ng / ml LPS and different concentrations of the inhibitor to be tested (formula (I)) were added for 24 hours, and the supernatant was extracted. The level of TNF-[alpha] in the supernatant due to activation of microglia will be tested using a commercial ELISA kit (BD Biosciences).

[0076] Example 2 of the present invention characterizes the inhibitory activity of lovastatin. The result is as Figure 4 shown, Figure 4 This is the inhibitory effect of lovastatin on the expression of BV-2 microglial inflammatory factor TNF-α in Example 2 of the present invention.

[0077] Depend on Figure 4 It can be seen that the inhibitor of...

Embodiment 3

[0079] (3) BV-2 microglia were cultured in a 37°C incubator (containing 5% carbon dioxide). Medium: DMEM+10% FBS; when the cell density reaches 90% full plate rate, passage. BV-2 microglia were resuspended in culture medium (cell density: 2 × 10 5 cells / ml) and plated in 96-well plates overnight. The medium was replaced with FBS-free DMEM, 200 ng / ml LPS and different concentrations of the inhibitor to be tested (formula (I)) were added, and 24 hours later, the supernatant was collected. The nitric oxide concentration was detected by 2,3-diaminonaphthalene fluorescence method.

[0080] Example 3 of the present invention characterizes the inhibitory activity of lovastatin. The result is as Figure 5 shown, Figure 5 This is the inhibitory effect of lovastatin on the release of nitric oxide in BV-2 microglia in Example 3 of the present invention.

[0081] Depend on Figure 5 It can be seen that the inhibitor formula (I) described in the present invention can significantly ...

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Abstract

The invention provides application of lovastatin to preparing Toll-like receptor 4 signaling pathway activation inhibitors and application of lovastatin to preparing microglial cell downstream inflammatory factor expression inhibitor and microglial cell inflammatory signaling pathway activation inhibitors. In vitro experiments prove that, in microglial cells processed and activated by endotoxins,the level of content of nitric oxide, hydrogen peroxide, reactive oxygen and inflammatory factors can be significantly increased; applied lovastatin can significantly inhibit release of nitric oxide,hydrogen peroxide and reactive oxygen and expression of the inflammatory factors; in BV-2 cells, the nitric oxide inhibiting activity of lovastatin is 11.6-13.8 mu M. In vivo experiments prove that lovastatin can reduce in vivo neuropathic pain of Sprague-Dawley rats and inhibit expression of a microglial cell activation marker of CD11b, thereby signifying the effects of lovastatin on specific regulation of microglial cell activation.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of lovastatin in the preparation of a microglia activation inhibitor. Background technique [0002] Microglia, a type of immune cell found in the brain and spinal cord, make up about 10% of all cells in the central nervous system (CNS). In addition to secreting neurotrophic factors, microglia play important roles in CNS homeostasis, including synaptic monitoring and trimming, proliferation, migration, and phagocytosis. Microglial dysfunction is associated with a variety of neuropathic diseases, including chronic pain, neurodegenerative diseases, and drug abuse; however, methods to specifically modulate microglial activation are currently limited. [0003] Toll-like receptor 4 (TLR4) is an innate immune receptor that is highly expressed in microglia. TLR4 recognizes exogenous pathogen-associated molecular patterns (PAMPs), endogenous damage-associated molecular ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/366A61P29/00A61P25/02
CPCA61K31/366A61P29/00A61P25/02
Inventor 王晓辉张晓铮
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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