CN110051666A - Lovastatin is preparing the application in Activated Microglia inhibitor - Google Patents
Lovastatin is preparing the application in Activated Microglia inhibitor Download PDFInfo
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- CN110051666A CN110051666A CN201910470041.XA CN201910470041A CN110051666A CN 110051666 A CN110051666 A CN 110051666A CN 201910470041 A CN201910470041 A CN 201910470041A CN 110051666 A CN110051666 A CN 110051666A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The present invention provides application of the Lovastatin in preparation 4 signal path activation inhibitor of Toll-like receptor.Lovastatin is provided simultaneously in the application in preparation microglia downstream inflammatory factor expression inhibitor, the application in microglia inflammatory signals signal pathway activated inhibitor.The present invention is confirmed by experiment in vitro, and in the microglia of endotoxin processing activation, nitric oxide, hydrogen peroxide, active oxygen and inflammatory factor are horizontal significantly to be increased；Give Lovastatin can significantly inhibit nitric oxide, hydrogen peroxide, the release of active oxygen and inflammatory factor expression.In BV-2 cell, the nitric oxide inhibitory activity of Lovastatin is 12.7 ± 1.1 μM.The present invention confirms that Lovastatin can reduce the expression of Sprague-Dawley rat nerves within the body pain and microglial activation marker CD11b by experiment in vivo.Mean effect of the Lovastatin in specific regulatory control Activated Microglia.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly, to Lovastatin in preparing Activated Microglia inhibitor
Application.
Background technique
Microglia is a kind of immunocyte being present in brain and spinal cord, accounts for about central nervous system (CNS) institute
There is the 10% of cell.Microglia plays in central nervous system balance and focuses on other than secretory nerve trophic factors
It acts on, including cynapse monitoring and finishing, proliferation, migration and phagocytosis.Microglia dysfunction with include chronic ache, mind
It is related to a variety of neuropathic diseases including drug abuse through degenerative disease；However the small colloid of specificity adjusting at present is thin
The method of born of the same parents' activation is also very limited.
Toll-like receptor 4 (TLR4) is a kind of innate immunity receptor highly expressed in microglia.TLR4 identification is outer
The pathogen associated molecular pattern (PAMPs) in source, endogenous damage associated molecular pattern (DAMPs) and heterologous object relevant molecule mould
The activation of formula (XAMPs), signal path is the key factor of Activated Microglia.Therefore, TLR4 is that the small colloid of research and development is thin
The important target spot of born of the same parents' regulator.
Since the 1990s, the small-molecule modulators of TLR4 and its auxilin marrow sample differentiation factor 2 (MD2) have been targeted
It is widely studied, many TLR4 small molecule modulators are come out one after another；However, wherein there is good blood-brain barrier to penetrate ability
Small molecule it is very rare, and without a kind of TLR4 small-molecule modulators pass through the clinical trial of III phase.This is largely hindered
The research and development of microglia regulator and potential neuropathic disease therapeutic agent are hindered.
Lovastatin is a kind of statins for reducing Blood Cholesterol, penetrating with good blood-brain barrier
Ability and clinical approval is obtained.The study found that Lovastatin can be identified by MD-2, it is a kind of potential TLR4 inhibitor.
Summary of the invention
In view of this, the present invention passes through experiment the technical problem to be solved in the present invention is that providing the application of Lovastatin
It was found that Lovastatin can be used for the activation of the TLR4 signal path of LPS induction, to inhibit Activated Microglia.
The present invention provides application of the Lovastatin in preparation 4 signal path activation inhibitor of Toll-like receptor.
The present invention provides application of the Lovastatin in preparation microglia downstream inflammatory factor expression inhibitor.
Preferably, the inflammatory factor includes one of IL-6, COX-2 and TNF-α or a variety of.
The present invention provides application of the Lovastatin in preparation microglia inflammatory signals signal pathway activated inhibitor.
Preferably, the inhibitor is for inhibiting No. 4 signal path activation, small colloids of Toll-like receptor as caused by LPS
Cell activation marker CD11b expression, inflammatory factor expression, nitric oxide, hydrogen peroxide or Active oxygen release.
Preferably, the Lovastatin is shown in formula I；
The present invention provides application of the Lovastatin in preparation prevention and treatment neurogenic pain drug.
Preferably, which is characterized in that the neurogenic pain includes living by nervus peripheralis damage or microglia
Pain caused by changing.
It include Lovastatin and pharmaceutically acceptable the present invention provides a kind of drug for preventing and treating neurogenic pain
Auxiliary material.
Preferably, the dosage form of the drug includes one of ejection preparation, oral preparation and spray formulation or a variety of.
Compared with prior art, the present invention provides Lovastatins inhibits in preparation 4 signal path of Toll-like receptor activation
Application in agent.Simultaneously provide Lovastatin preparation microglia downstream inflammatory factor expression inhibitor in application,
Application in microglia inflammatory signals signal pathway activated inhibitor.The present invention is confirmed by experiment in vitro, at endotoxin (LPS)
In the microglia for handling activation, the horizontal significant raising of nitric oxide, hydrogen peroxide, active oxygen and inflammatory factor；Give Lip river
Cut down statin can significantly inhibit nitric oxide, hydrogen peroxide, the release of active oxygen and inflammatory factor expression.In BV-2 cell, Lip river
The nitric oxide inhibitory activity for cutting down statin is 12.7 ± 1.1 μM；And it is to the astroglia of LPS induction, in nervous centralis
Chrotoplast and macrophage activation are without apparent inhibiting effect.The present invention confirms that Lovastatin can reduce by experiment in vivo
The expression of Sprague-Dawley rat nerves within the body pain and microglial activation marker CD11b.Mean that Lip river is cut down
Key effect of the statin in specific regulatory control Activated Microglia.
There is compound Lovastatin of the present invention good blood-brain barrier to penetrate ability.Experimental data shows Lip river
It cuts down statin to play an important role in the Activated Microglia that TLR4 is mediated, it is considered to be Activated Microglia inhibits
Agent.The present invention will provide effective therapy approach for neurogenic pain.
Detailed description of the invention
Fig. 1 is the mRNA that Lovastatin inhibits inflammatory factor IL-6 in BV-2 microglia in a manner of dose-dependent
Expression；
Fig. 2 is that Lovastatin inhibits inflammatory factor COX-2's in BV-2 microglia in a manner of dose-dependent
MRNA expression；
Fig. 3 is that Lovastatin inhibits inflammatory factor TNF-α in BV-2 microglia in a manner of dose-dependent
MRNA expression；
Fig. 4 is that Lovastatin inhibits inflammatory factor TNF-α to express in BV-2 microglia in a manner of dose-dependent；
Fig. 5 is that Lovastatin can significantly inhibit the activation of TLR4 signal path in BV-2 microglia and nitric oxide is released
It puts；
Fig. 6 be Lovastatin inhibited in a manner of dose-dependent in BV-2 microglia TLR4 signal path activation and
Hydrogen peroxide release；
Fig. 7 is that Lovastatin can significantly inhibit the activation of TLR4 signal path in BV-2 microglia and active oxygen is released
It puts；
Fig. 8 is that Lovastatin can significantly mitigate neuropathic pain in Sprague-Dawley rat body；
Fig. 9 is that Lovastatin can significantly reduce microglial activation marker in Sprague-Dawley rat body
The expression of CD11b.
Specific embodiment
The present invention provides the application of Lovastatin, those skilled in the art can use for reference present disclosure, suitably be changed
Into realization.In particular, it should be pointed out that all similar substitutions and modifications are apparent to those skilled in the art,
They shall fall within the protection scope of the present invention.Method and application of the invention is described by preferred embodiment, phase
Pass personnel can obviously not depart from the content of present invention, be modified to methods herein and application in spirit and scope or suitably become
More with combine, carry out implementation and application the technology of the present invention.
The present invention provides application of the Lovastatin in preparation 4 signal path activation inhibitor of Toll-like receptor.
According to the present invention, the inhibitor is preferred for inhibiting the microglia TLR4 signal path as caused by LPS living
Change.
The present invention provides Lovastatins to prepare the application in Activated Microglia inhibitor.
TLR4 preferred expression of the present invention is in BV-2 microglia.
Shown in Lovastatin of the present invention such as formula (I):
For the present invention to its source without limiting, prepared by commercially available or method according to prior art routine.
Microglia is the immunocyte being present in brain and spinal cord, and it is all thin to account for about central nervous system (CNS)
The 10% of born of the same parents.Microglia plays important work in central nervous system balance other than secretory nerve trophic factors
With, including cynapse monitoring and finishing, proliferation, migration and phagocytosis.Microglia dysfunction is moved back with including chronic ache, nerve
Row disease is related to a variety of neuropathic diseases including drug abuse；However specificity adjusts microglia at present
Method is also very limited.
Toll-like receptor 4 (TLR4) is a kind of innate immunity receptor highly expressed in microglia.TLR4 identification is outer
The pathogen associated molecular pattern (PAMPs) in source, endogenous damage associated molecular pattern (DAMPs) and heterologous object relevant molecule mould
Formula (XAMPs) is the key factor of Activated Microglia.Therefore, TLR4 is the important target for researching and developing microglia regulator
Point.
Prior art discloses many TLR4 small molecule modulators；However, wherein there is good blood-brain barrier to penetrate ability
Small molecule it is very rare, and without a kind of TLR4 small-molecule modulators pass through the clinical trial of III phase.
The present inventor experiments prove that Lovastatin played during the Activated Microglia that TLR4 is mediated it is important
Effect, be main Activated Microglia inhibitor.
The present invention by external Activated Microglia signal nitric oxide, hydrogen peroxide, active oxygen and downstream inflammation because
Son detection discovery, Lovastatin have significant inhibiting effect, and Lovastatin to the Activated Microglia that TLR4 is mediated
Different inhibitory activity is shown to different spongiocytes.
The present invention experiments prove that, in BV-2 cell, nitric oxide inhibitory activity be 12.7 ± 1.1 μM；And him is cut down in Lip river
Astroglia, nervous centralis endothelial cell and the macrophage activation that spit of fland induces LPS are without apparent inhibiting effect.Meaning
Key effect of the Lovastatin in specific regulatory control Activated Microglia.
The present invention provides application of the Lovastatin in preparation microglia downstream inflammatory factor expression inhibitor.
According to the present invention, the inflammatory factor includes one of IL-6, COX-2 and TNF-α or a variety of.
According to the present invention, the inhibitor is preferred for inhibiting the inflammatory factor expression as caused by LPS or nitric oxide, mistake
Hydrogen oxide, Active oxygen release.
The present inventor experiments prove that, inhibitor formula (I) described in the invention can significantly inhibit nitric oxide releasing
Amount, inhibitory activity are 12.7 ± 1.1 μM.
Inhibitor formula (I) described in the invention inhibits hydrogen peroxide burst size in a manner of dose-dependent.
Inhibitor formula (I) energy remarkable inhibiting activity oxygen evolution amount described in the invention, inhibitory activity 0.9
±0.1μM。
The present invention is confirmed by experiment in vitro, in the microglia of endotoxin (LPS) processing activation, nitric oxide,
The horizontal significant raising of hydrogen peroxide, active oxygen and downstream inflammatory factor.Nitric oxide, peroxide can be significantly inhibited by giving Lovastatin
Change the release of hydrogen and active oxygen and the expression of downstream inflammatory factor.
The present invention provides application of the Lovastatin in preparation microglia inflammatory signals signal pathway activated inhibitor.
In the present invention, the inhibitor activates for inhibition No. 4 signal paths of Toll-like receptor as caused by LPS, is small
Microglia activation marker CD11b expression, inflammatory factor expression, nitric oxide, hydrogen peroxide or Active oxygen release.
The present invention confirms that Lovastatin can reduce Sprague-Dawley rat nerves within the body pain by experiment in vitro
With the expression of microglial activation marker CD11b.
The present invention provides Lovastatins to prepare answering in microglial activation marker CD11b expression inhibiting agent
With.
Lovastatin can significantly inhibit the mRNA expression of inflammatory factor IL-6 in BV-2 microglia；Lovastatin exists
The mRNA expression of inflammatory factor COX-2 can be significantly inhibited in BV-2 microglia；Lovastatin is in BV-2 microglia
The mRNA expression of inflammatory factor TNF-α can be significantly inhibited.
The present invention by confirm above-mentioned Lovastatin can significantly inhibit nitric oxide, hydrogen peroxide, Active oxygen release and under
The expression for swimming inflammatory factor, to confirm that Lovastatin is able to suppress microglia inflammatory signals signal pathway activated.
Shown in Lovastatin of the present invention such as formula (I)；
The Lovastatin of formula (I) structure of the present invention, which can mark, is.
For the present invention to its source without limiting, prepared by commercially available or method according to prior art routine.
The present invention provides application of the Lovastatin in preparation prevention and treatment neurogenic pain drug.
Neurogenic pain of the present invention includes the pain as caused by nervus peripheralis damage or Activated Microglia.
The present invention provides a kind of drugs for preventing and treating neurogenic pain, including Lovastatin and pharmaceutically acceptable
Auxiliary material.
According to the present invention, the dosage form of the drug includes one of ejection preparation, oral preparation and spray formulation or more
Kind.The present invention for the pharmaceutically acceptable auxiliary material without limit, it is well known to those skilled in the art.
The present invention also provides application of the Lovastatin in the health care product that preparation improves neurogenic pain.
The present invention provides application of the Lovastatin in preparation 4 signal path activation inhibitor of Toll-like receptor.Simultaneously
It provides Lovastatin and is preparing the application in the inflammatory factor expression inhibitor of microglia downstream, microglia inflammation letter
Application in number signal pathway activated inhibitor.The present invention is confirmed by experiment in vitro, in the small colloid of endotoxin (LPS) processing activation
In cell, the horizontal significant raising of nitric oxide, hydrogen peroxide, active oxygen and inflammatory factor；Giving Lovastatin can significantly inhibit
Nitric oxide, hydrogen peroxide, the release of active oxygen and inflammatory factor expression.In BV-2 cell, the nitric oxide of Lovastatin
Inhibitory activity is 12.7 ± 1.1 μM；And its astroglia, nervous centralis endothelial cell and macrophage to LPS induction
Activation is without apparent inhibiting effect.The present invention confirms that Lovastatin can reduce Sprague-Dawley rat by experiment in vivo
The expression of nerves within the body pain and microglial activation marker CD11b.Mean that Lovastatin is small in specific regulatory control
Key effect in Glial Activation.
There is compound Lovastatin of the present invention good blood-brain barrier to penetrate ability.Experimental data shows Lip river
It cuts down statin to play an important role in the Activated Microglia that TLR4 is mediated, it is considered to be Activated Microglia inhibits
Agent.The present invention will provide effective therapy approach for neurogenic pain.
In order to further illustrate the present invention, binary naltrexone derivative provided by the invention is answered with reference to embodiments
With being described in detail.
For the present invention to its source without limiting, prepared by commercially available or method according to prior art routine.
Embodiment 1
(1) BV-2 microglia cultivates (carbon dioxide containing 5%) in 37 DEG C of incubator.Culture medium: DMEM+
10%FBS；When cell density reaches 90% full plate rate, passage.BV-2 microglia is resuspended in culture medium (cell density: 2
×105Cells/ml), 96 orifice plates are plated on to stay overnight.The DMEM of no FBS is replaced medium to, 200ng/mlLPS and difference is added
The testing inhibitor (formula (I)) of concentration after 24 hours, extracts RNA.By qPCR instrument (Analytik Jena, Thuringia,
Germany the mrna expression amount of IL-6, COX-2 and TNF-α therein) are detected.
The embodiment of the present invention 1 characterizes Lovastatin inhibitory activity.As a result as shown in Figure 1, Figure 2 and Figure 3, wherein scheming
1 imitates for inhibition of the Lovastatin in the embodiment of the present invention 1 for the mRNA expression of inflammatory factor IL-6 in BV-2 microglia
Fruit；Fig. 2 is mRNA expression of the Lovastatin for inflammatory factor COX-2 in BV-2 microglia in the embodiment of the present invention 1
Inhibitory effect；Fig. 3 is Lovastatin in the embodiment of the present invention 1 for the mRNA of inflammatory factor TNF-α in BV-2 microglia
The inhibitory effect of expression.
By Fig. 1, Fig. 2 and Fig. 3 it is found that inhibitor formula (I) described in the invention inhibits BV-2 in a manner of dose-dependent
The expression of small colloid downstream inflammatory factor IL-6, COX-2 and the mRNA of TNF-α.
Embodiment 2
(2) BV-2 microglia cultivates (carbon dioxide containing 5%) in 37 DEG C of incubator.Culture medium: DMEM+
10%FBS；When cell density reaches 90% full plate rate, passage.BV-2 microglia is resuspended in culture medium (cell density: 2
×105Cells/ml), 96 orifice plates are plated on to stay overnight.The DMEM of no FBS is replaced medium to, 200ng/mlLPS and difference is added
The testing inhibitor (formula (I)) of concentration drug effect 24 hours extracts supernatant.It is generated in supernatant due to Activated Microglia
The test of TNF-α level will be tested using commercial ELISA Kit (BD Biosciences).
The embodiment of the present invention 2 characterizes Lovastatin inhibitory activity.As a result as shown in figure 4, Fig. 4 is that the present invention is implemented
The inhibitory effect that Lovastatin expresses BV-2 microglia inflammatory factor TNF-α in example 2.
As shown in Figure 4, inhibitor formula (I) described in the invention inhibits BV-2 microglia in a manner of dose-dependent
The expression of downstream inflammatory factor TNF-α.
Embodiment 3
(3) BV-2 microglia cultivates (carbon dioxide containing 5%) in 37 DEG C of incubator.Culture medium: DMEM+
10%FBS；When cell density reaches 90% full plate rate, passage.BV-2 microglia is resuspended in culture medium (cell density: 2
×105Cells/ml), 96 orifice plates are plated on to stay overnight.It replaces medium to the DMEM of no FBS, 200ng/ml LPS and not is added
With the testing inhibitor (formula (I)) of concentration, after 24 hours, supernatant is collected.Pass through 2,3- diaminonaphthalene (2,3-
Diaminonaphthalene) fluorescent method detects nitric oxide concentration therein.
The embodiment of the present invention 3 characterizes Lovastatin inhibitory activity.As a result as shown in figure 5, Fig. 5 is that the present invention is implemented
Inhibitory effect of the Lovastatin for nitric oxide releasing in BV-2 microglia in example 3.
As shown in Figure 5, it is living to significantly inhibit microglia inflammatory signals access to inhibitor formula (I) described in the invention
Change, inhibitory activity is 12.7 ± 1.1 μM.
Embodiment 4
(4) BV-2 microglia cultivates (carbon dioxide containing 5%) in 37 DEG C of incubator.Culture medium: DMEM+
10%FBS；When cell density reaches 90% full plate rate, passage.BV-2 microglia is resuspended in culture medium (cell density: 2
×105Cells/ml), 96 orifice plates are plated on to stay overnight.It replaces medium to the DMEM of no FBS, 200ng/ml LPS and not is added
With the testing inhibitor (formula (I)) of concentration, after 24 hours, supernatant is collected.Pass through Pierre's Si peroxide reagent box (Pierce
Quantitative Peroxide Assay kit) detection concentration of hydrogen peroxide therein.
The embodiment of the present invention 4 characterizes Lovastatin inhibitory activity.As a result as shown in fig. 6, Fig. 6 is that the present invention is implemented
The inhibitory effect that Lovastatin discharges hydrogen peroxide in BV-2 microglia in example 4.
It will be appreciated from fig. 6 that inhibitor formula (I) described in the invention inhibits microglia inflammation in a manner of dose-dependent
Signal path activation.
Embodiment 5
(5) BV-2 microglia cultivates (carbon dioxide containing 5%) in 37 DEG C of incubator.Culture medium: DMEM+
10%FBS；When cell density reaches 90% full plate rate, passage.BV-2 microglia is resuspended in culture medium (cell density: 2
×105Cells/ml), 96 orifice plates are plated on to stay overnight.It replaces medium to the DMEM of no FBS, 200ng/ml LPS and not is added
Testing inhibitor ((+) -1 or (-) -1) with concentration passed through nitroblue tetrazolium (NBT) (Nitroblue after 24 hours
Tetrazolium, NBT) fluorescent method detection active oxygen (superoxides) concentration therein.
The embodiment of the present invention 5 characterizes Lovastatin inhibitory activity.As a result as shown in fig. 7, Fig. 7 is that the present invention is implemented
The inhibitory effect that Lovastatin discharges active oxygen (superoxides) in BV-2 microglia in example 5.
As shown in Figure 7, it is living to significantly inhibit microglia inflammatory signals access to inhibitor formula (I) described in the invention
Change, inhibitory activity is 0.9 ± 0.1 μM.
Embodiment 6
(6) experiment be all made of no pathogenicity bull Sprague-Dawley rat (300-350g) and by it is intrathecal to
Prescription formula is administered, daily administration 50 μ g, and successive administration 3 days.The chronic constriction injury mould damaged using Partial Sciatic
Type (CCI) carries out drug neuropathic pain Activity determination；
The embodiment of the present invention 6 characterizes analgesic activity in Lovastatin body.As a result as shown in figure 8, Fig. 8 is this
Lovastatin mitigates Sprague-Dawley neuropathic pain in rats and microglial activation marker in inventive embodiments 6
The inhibitory effect of expression.
Embodiment 7
(7) experiment be all made of no pathogenicity bull Sprague-Dawley rat (300-350g) and by it is intrathecal to
Prescription formula is administered, daily administration 50 μ g, and successive administration 3 days.Using immunohistochemistry technology to Sprague-Dawley
The microglia marker CD11b of the notochord (L4-L6) of rat carries out semi-quantitative analysis.
The embodiment of the present invention 7 characterizes microglia activity in Lovastatin body.As a result as shown in figure 9, Fig. 9 is
Lovastatin reduces the inhibitory effect of the expression of microglial activation marker in the embodiment of the present invention 7.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. application of the Lovastatin in preparation 4 signal path activation inhibitor of Toll-like receptor.
2. application of the Lovastatin in preparation microglia downstream inflammatory factor expression inhibitor.
3. application according to claim 2, the inflammatory factor includes one of IL-6, COX-2 and TNF-α or more
Kind.
4. application of the Lovastatin in preparation microglia inflammatory signals signal pathway activated inhibitor.
5. application according to claims 1 to 4, the inhibitor is for inhibiting Toll-like receptor 4 letters as caused by LPS
Number signal pathway activated, microglial activation marker CD11b expression, inflammatory factor expression, nitric oxide, hydrogen peroxide or activity
Oxygen evolution.
6. application described in any one according to claim 1~4, which is characterized in that the Lovastatin is shown in formula I；
7. application of the Lovastatin in preparation prevention and treatment neurogenic pain drug.
8. application according to claim 7, which is characterized in that the neurogenic pain includes being damaged by nervus peripheralis
Or pain caused by Activated Microglia.
9. a kind of drug for preventing and treating neurogenic pain, which is characterized in that including Lovastatin and pharmaceutically acceptable auxiliary
Material.
10. drug according to claim 9, which is characterized in that the dosage form of the drug includes ejection preparation, oral preparation
With one of spray formulation or a variety of.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910470041.XA CN110051666A (en) | 2019-05-31 | 2019-05-31 | Lovastatin is preparing the application in Activated Microglia inhibitor |
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| CN201910470041.XA CN110051666A (en) | 2019-05-31 | 2019-05-31 | Lovastatin is preparing the application in Activated Microglia inhibitor |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114146092A (en) * | 2021-11-15 | 2022-03-08 | 青岛农业大学 | Hyaluronic acid fragment, application of preparation thereof and quality control activity detection method |
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| WO2006124676A1 (en) * | 2005-05-17 | 2006-11-23 | The Interthyr Corporation | Methods and compositions for the treatment of autoimmune and inflammatory diseases associated with toll-like receptors |
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