CN108685903B - Application of the carnosol in preparation prevention and treatment experimental autoimmune encephalomyelitis drug - Google Patents
Application of the carnosol in preparation prevention and treatment experimental autoimmune encephalomyelitis drug Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The invention discloses application of the carnosol in preparation prevention and treatment experimental autoimmune encephalomyelitis drug, with whole animal model experiment, the generation and development of experimental autoimmune encephalomyelitis can not only effectively be delayed by demonstrating carnosol, significantly reduce infiltration from peripheral inflammation cell to central nervous system, mitigate demyelinate degree, moreover it is possible to promote infiltration macrophage and M2 phenotype from the proinflammatory phenotype of intrinsic microglia to immunoloregulation function transformation.In addition, carnosol can inhibit Th17 cell differentiation and STAT3 phosphorylation, and block transcription factor NF-KB core transposition.Therefore, the drug that carnosol is used to prepare prevention and treatment autoimmune disease such as multiple sclerosis has huge potentiality.
Description
Technical field
The invention belongs to biomedical and medicinal application field, in particular to carnosol preparation prevention and treatment it is experimental itself
The application of allergic encephalomyelitis drug.
Background technique
Multiple sclerosis (Multiple Sclerosis, MS) and its animal model experimental autoimmune myelencephalon
Scorching (Experimental Autoimmune Encephalomyelitis, EAE) is a kind of immunocyte activated by itself
It acts on caused by central nervous system (Central Nervous System, CNS) with inflammatory cell infiltration and myelinoclasis
For the neurodegenerative disease of characteristic feature.MS clinical symptoms are mainly shown as eye-blurred, body numbness, quadriplegia etc.,
It is mainly in younger population, and is difficult to cure, there is very high disability rate, the whole world is distributed at present, has had more than 2,500,000
People suffers from this disease, and the disease incidence in China also improves year by year, there is the title of not dead cancer.
The pathogenesis of MS not yet illustrates completely so far, wherein Th17 cell is by generating proinflammatory cytokine (IL-
17A, IL-17F, GM-CSF and IL-22) become inflammation and autoimmune disease Primary Actor, the differentiation of Th17 cell and
The generation of relevant cell factor is directly controlled by ROR γ t, and the coherent signal for regulating and controlling Th17 cell differentiation can inhibit modulability
T cell (Treg) differentiation, therefore, exploitation targeted inhibition ROR γ t transcription or Th17 differentiation associated signal paths such as NF- κ B and
The drug of STAT3 is expected to provide new therapeutic strategy for the disease that treatment Th17 is mediated.Have at present for the drug of MS treatment
Limit, finds a kind of novel drugs of selectively targeted pathogenic T h17 cell of energy, while retaining other immunocytes, for more effective
Treatment MS it is particularly significant.In recent years, scientific research personnel constantly explore from medicinal and food plant native compound and its
The novel anti-inflammatory or immunoregulation medicament of derivative, they have great potential in terms for the treatment of autoimmune disease.
Carnosol is a kind of natural diterpene compound being present in the plants such as rosemary and Radix Salviae Miltiorrhizae, and alias is Salvia japonica
Bitter lactones, the entitled carnosol of English, carnosol have very strong reducing blood lipid, anti-oxidant, antitumor, antiviral and anti-inflammatory spy
Property, it is widely used in the fields such as health care, food, natural pigment, cosmetics, it was reported that carnosol can be by inhibiting NF- κ B
Access and have antineoplastic action, with inducing T cell leukaemia, lymphoma cell apoptosis and the IL-6 in serum can also be reduced
With TNF-α level.So it is the natural active compound that new drug research person compares favor in recent years, however can it
It plays a role and has not been reported in prevention and treatment experimental autoimmune encephalomyelitis.
Summary of the invention
The object of the present invention is to provide carnosols in preparation prevention and treatment experimental autoimmune encephalomyelitis drug
Using.
In order to realize above-mentioned task, applicant carried out whole animal model experiments, it was demonstrated that carnosol can be effectively
The generation and development for delaying experimental autoimmune encephalomyelitis can be used for preparing prevention and treatment experimental autoimmune myelencephalon
Scorching drug.
Further, the structural formula of the carnosol is as follows:
The drug of the prevention and treatment experimental autoimmune encephalomyelitis is the drug for preventing and treating multiple sclerosis, the medicine
Object is inhibited needed for Th17 cell differentiation by inhibiting CD4+ T cell to play its immune function to Th17 cell differentiation
The phosphorylation of STAT3 and NF- κ B.
Carnosol can improve the coincident with severity degree of condition of experimental autoimmune encephalomyelitis, promote Remyelination.Also
The macrophage that can make infiltration and intrinsic microglia are from proinflammatory (M1) to the M2 Phenotype Transition with immunoloregulation function.
Therefore, the drug that carnosol is used to prepare prevention and treatment autoimmune disease such as multiple sclerosis has huge
Potentiality.
Detailed description of the invention
Fig. 1 is PBS control group and carnosol prevention group mouse invasion clinical score comparison diagram.
Fig. 2 is that the 30th day spinal cord waist sacrum cyrtosis of PBS control group and carnosol prevention group manages slice map (a), and assesses
The pathological score of inflammation and the chart of percentage comparison (b, c) of demyelinating area.
Fig. 3 is PBS control group and carnosol prevention group spinal cord immunofluorescence dyeing figure (a), analyzes MBP ELISA
(MBP) quantity figure (b, c) of staining power and CD45+ cell.
Fig. 4 is that counting PBS control group and the monokaryon in carnosol prevention group central nervous system are thin under optical microscopy
Born of the same parents' sum spirogram (a), the percentage of Flow cytometry CD4+T cell when calculate the CD4+T of infiltration absolute number spirogram (b,
c)。
Fig. 5 is CD4+ cell streaming testing result figure (a- in PBS control group and carnosol prevention group central nervous system
D), and its secretion cell factor and inflammatory factor enzyme-linked immunosorbent assay result figure (e).
Fig. 6 is enzyme-linked immunosorbent assay analysis chart.Detect PBS control group and the 30th day splenocyte of carnosol prevention group
Cultivate supernatant liquor Cytokine Expression Level.
Fig. 7 is fluidic cell result figure (a-d).Separate C57BL/6J mouseCD4+ cell detects various concentration
Relevant cell expression of results after carnosol processing.
Fig. 8 is immunoblotting assay figure (a-c).It is cultivated under Th17 polarization conditionCD4+T cell, and with 10 μM
Carnosol and PBS detect NF- κ B and STAT3 expression in cell after handling 3 days.
Fig. 9 is that real-time fluorescence quantitative PCR measurement PBS control group is opposite with carnosol processing group proinflammatory cytokine mRNA
Expression figure (a, b).
Figure 10 is PBS control group and carnosol processing group mice clinical appraisal result figure in adoptive transfer experiment.
Figure 11 is the 20th day execution mouse in adoptive transfer experiment, to PBS control group and carnosol processing group brain group
Knit slice carry out CD45+GFP+ cell immunofluorescence dyeing figure (a) and the total CD45+ cell quantity chart of percentage comparison of their Zhan (b,
c)。
Figure 12 is PBS control group and clinical score figure of the carnosol treatment group mouse in the stage that chronic EAE is fallen ill.
Figure 13 is PBS control group and the 60th day mouse spinal cord lumbosacral enlargement pathological section of carnosol treatment group and myelin alkali
Property protein staining figure (a-f).
Figure 14 is that macrophage and microglia promote in PBS control group and the 60th day mouse spinal cord of carnosol treatment group
The MBP ELISA dyeing of scorching (M1), immunological regulation (M2) marker and double positive cells percentage quantitative analysis figure (a-d).
Figure 15 is enzyme-linked immunosorbent assay detection and real-time fluorescence quantitative PCR testing result figure.Simultaneously from new life
Primary microglia is prepared in C57BL/6J mouse, is stimulated with lipopolysaccharides (LPS) and handles 2 with the carnosol of various concentration
Enzyme-linked immunosorbent assay figure (a), real-time fluorescence quantitative PCR testing result figure (b) after it.
Experimental autoimmune encephalomyelitis is prevented and treated in preparation to carnosol below by the drawings and specific embodiments
Application in drug is described in detail.
Specific embodiment
The carnosol that the present embodiment provides is a kind of naturalization that be potential, can be used as treating multiple sclerosis disease
Close object, it can also be used to treat other autoimmune diseases.
Carnosol is the natural constituent of draft medicinal plant, has structure below:
In order to study whether carnosol can prepare the application for preventing and treating experimental autoimmune encephalomyelitis drug,
Applicant carried out whole animal model experiments below:
(1) carnosol is used to improve the experiment of experimental autoimmune encephalomyelitis:
According to a conventional method, C57BL/6J mouse is selected, myelin oligodendroglia glycoprotein peptide is established35-55(MOG35-55)
The experimental autoimmune encephalomyelitis model of induction；Modeling same day beginning carries out intraperitoneal injection with carnosol daily and gives
Medicine carries out clinical score, observation nervous function performance to mouse invasion situation daily；After experiment, experiment mice point is put to death
It is used for tissue section strain from periphery and central nervous system tissue, and passes through flow cytometry, enzyme-linked immunosorbent assay
(ELISA) detection carnosol is to maincenter and periphery immune response situation.In addition it is small to be isolated from normal C57BL/6J for experiment in vitro
MouseCD4+ induced t cell Th17 cell differentiation, while carnosol processing is given to illustrate carnosol pair
The mechanism that CD4+ T cell subgroup influences, and pass through western blotting method analysis of key signaling molecule.
The result shows that carnosol can improve the clinical severity of experimental autoimmune encephalomyelitis, inhibit
Th17 cell differentiation and STAT3 phosphorylation, and block transcription factor NF-KB core transposition.
(2) carnosol adoptive transfer experiment:
Identical as (1) modeling administration, after modeling the 10th day spleen from IL-17A-IRES-GFP mouse (C57BL/6J) and
Influence of the mononuclearcell research carnosol to Th17 cytopathic is prepared in lymph node.
The result shows that carnosol can inhibit the differentiation of Th17 pathogenic cells.
(3) carnosol is used to improve the experiment of chronic experi Autoimmune Encephalomyelitis:
Modeling administration identical as (1), mouse is treated since the 25th day, carries out clinical score.After experiment, to mouse
Fixation, paraffin embedding, tissue section strain is perfused, observes pathologic condition.
The result shows that carnosol can improve the coincident with severity degree of condition of chronic experi Autoimmune Encephalomyelitis, promote
Into Remyelination.The macrophage that can also make infiltration and intrinsic microglia are from proinflammatory (M1) to immunoloregulation function
M2 Phenotype Transition.
It is above-mentioned the experimental results showed that, carnosol can effectively improve myelin oligodendrocyte glycoprotein peptide35-55
(MOG35-55) induction experimental autoimmune encephalomyelitis model in clinical disease seriousness, significantly reduce inflammatory cell
To central nervous system infiltration and reduce demyelinate degree, moreover it is possible to promote infiltration macrophage or microglia phenotype
From proinflammatory (M1) to the Phenotype Transition of the M2 with immunoloregulation function.In addition, giving carnosol processing can effectively inhibit
Th17 cell differentiation and STAT3 phosphorylation, and block transcription factor NF-KB core transposition.The carnosol is a kind of potential
, native compound that can be used as treating multiple sclerosis disease, it can also be used to treat other autoimmune diseases.
It is the specific embodiment that inventor provides below:
Material therefor, reagent, instrument and method in following embodiment can be obtained without specified otherwise by commercial channel
?.All experimental arrangements and scheme are ratified by the care of animal of Shaanxi Normal University and the committee, and according to the mechanism of approval
Guilding principle and regulations carry out.Statistical analysis processing uses 6 software of Graph Pad Prism (Graph Pad, La
Jolla, CA) carry out statistical analysis.Data are indicated with average value ± SD.When more multiple groups, data are multiple by Tukey
The variance analysis (ANOVA) for comparing test is analyzed.All statistical analysis are all made of the conspicuousness standard of p < 0.05.
Embodiment 1:
1, experiment process
(1) prepared by EAE model
Eight weeks female C57BL/6J mouse are purchased from army medical university, PLA Air Force (Chinese Xi'an).Myelin
Oligodendroglia glycoprotein peptide35-55(MOG35-55), it is purchased from Genescript company, pertussis toxin is purchased from Sigma-
Aldrich, the complete Freund's adjuvant containing mycobacterium tuberculosis are purchased from BD Difco company.
MOG is dissolved with PBS35-55Polypeptide, it is then mixed with isometric complete Freund's adjuvant (mycobacterium tuberculosis containing 5mg/ml)
It closes, pushes away the white antigen emulsion beaten to Water-In-Oil shape with glass syringe.
Mouse is immunized in two sites at back, respectively in intraperitoneal injection pertussis dilution on the day of being immunized and after 2 days
(200ng/ is only).
Grouping and administration:
1. the control group of PBS processing: starting to carry out intraperitoneal injection daily on the day of modeling.
2. carnosol processing group: starting to carry out intraperitoneal injection with carnosol (50mg/kg) daily on the day of modeling.
2, experiment post-processing:
(1) EAE standards of grading:
After mouse immune, Neuroscore is carried out to experimental animal daily, it then follows double blind principle observes its limbs strength
Situation simultaneously carries out clinical score.EAE clinical symptoms are referring to following standard: 0 point (without obvious clinical symptoms)；1 point (tail entirely without
Tension, hangover)；2 points (hind limb paralysis or double hind leg semi-paralysis)；3 points (hind leg is paralysed)；4 points (trunk paralysis)；5 points (are on the point of
It is dead or dead).
(2) tissue staining and pathology assessment
The mouse for taking modeling the 30th day, fixes through heart perfusion, takes spinal cord lumbosacral enlargement, paraffin embedding, do haematoxylin-she
Red (Hematoxylin-eosin, H&E) is dyed to assess inflammation, with Lao Kejian labor blue (Luxol fast blue, LFB) dyeing
Demyelinate degree is observed, the blind inflammation for commenting slice of 0-3 grades of standards of grading and demyelinate degree are used；For determining for myelinoclasis
Amount assessment, manually selects total white matter region, calculates demyelinating area with Image-Pro Plus software.Spinal cord is exempted from simultaneously
Epidemic disease fluorescent staining analysis.
(3) influence that evaluation carnosol infiltrates pathogenic T cell to CNS separates mononuclearcell from CNS on the 30th day
(Mononuclear cell, MNC) and the phenotype for passing through flow cytometry cell.
(4) cell factor production in PBS group and carnosol processing group periphery immune system is measured with ELISA.
(5) carnosol and PBS processing are from normal C57BL/6J mouseCD4+ T cell, illustrates Salvia japonica
The mechanism that phenol influences CD4+ T cell subgroup.
(6) it is purified from carnosol processing group and PBS processing group mouseCD4+ T cell obtains protein example,
And pass through immunoblotting assay key signal molecule.
3, experimental result
(1) compared with the control group of PBS processing, disease severity (Fig. 1) is substantially reduced after daily administration carnosol.
Spinal cord lumbosacral enlargement area immunohistology coloration result analysis in (2) the 30th days, compared with PBS processing, carnosol
A large amount of inflammatory infiltrations and demyelinate phenomenon are relatively light (Fig. 2) in processing group spinal cord.These are the result shows that carnosol has acute EAE
There is significant inhibiting effect.
(3) there are a large amount of CD45+ inflammatory cells, carnosol processing group in CNS tissue slice display PBS processing group focal area
Inflammatory cell quantity is substantially reduced (Fig. 3 a, Fig. 3 b) in slice, and demyelinate degree also substantially reduces (p < 0.01, Fig. 3 a, figure
3c).These results and HE and LFB dyeing are consistent, show that carnosol inhibits the inflammatory cell infiltration and demyelinate in CNS.
(4) by flow cytomery, compared with the control group of PBS processing, carnosol processing significantly reduces CNS
In MNC quantity (p < 0.01；Fig. 4 a), also reduce the percentage of CD4+ cell and absolute quantity (Fig. 4 b, Fig. 4 c) in CNS.
The percentage of CD4+IL17+ and CD4+GM-CSF+ cell significantly reduces (p < 0.001 after carnosol processing；Fig. 5 a- Fig. 5 e).
These are the result shows that carnosol may play a significant role in inhibiting CNS inflammatory infiltration, especially in Th17 cell mass
Effect is significant.
(5) splenocyte ELISA the result shows that, IL-17 and GM-CSF in carnosol processing group cell culture supernatant
Concentration significantly reduces (Fig. 6).Illustrate that carnosol specificity inhibits the generation of the pathogenicity Th17 Cellular inflammatory factor.
(6) under Th17 differentiation condition, compared with PBS group, carnosol processing group substantially reduces the differentiation of Th17 cell
(25.06 ± 2.13% couples of 4.47 ± 0.52%, p < 0.01) (Fig. 7 a, Fig. 7 d), and be in dose dependent.Carnosol processing
(Fig. 7 b- figure is had no significant effect to the expression of the IFN-γ or Foxp3 that generate under the conditions of Th1 cell and Treg cell differentiation
7d).These statistics indicate that carnosol selective depression Th17 differentiation.
(7) immunoblotting assay shows that carnosol can inhibit response of the cell to NF- κ Bp65 to nucleus transfer signal
(Fig. 8 a, Fig. 8 b), the proinflammatory secretion (Fig. 9 a) of reduction NF- κ B signal passage downstream, inhibition STAT3 activation (Fig. 8 a,
Fig. 8 c) and reduce IL-17 Cellular inflammatory cytokine secretion (Fig. 9 b).
Embodiment 2:
1. experiment process
Modeling same as Example 1 administration, after modeling the 10th day from IL-17A-IRES-GFP mouse (C57BL/6J)
Pathogenic influence of the MNC research carnosol to Th17 cell is prepared in spleen and lymph node, cell is existed with PBS and carnosol
It is cultivated under Th17 differentiation condition, and uses MOG35-55(25 μ g/ml), IL-2 (2ng/ml) and IL-23 (10ng/ml) stimulation.Culture
After three days, CD4+ T cell is separated.By the cell (4 × 106Cells it) is injected intoC57BL/6J Recipient mice.After 20 days
Mouse is put to death, collects different groups of brain tissue for immunohistochemical staining.
2. experimental result
(1) compared with PBS processing group, the tight of clinical disease is significantly reduced after the Th17 cell transfer of carnosol processing
Weight degree (p < 0.01；Figure 10).
The immunofluorescence dyeing of mouse is put to death after (2) the 20th days the results show that GFP+CD45+ is thin in carnosol processing group
The percentage of born of the same parents significantly reduces (p < 0.01；Figure 11 a- Figure 11 c).These vivo results further demonstrate carnosol to MOG
The pathogenic of Th17 cell of stimulation has inhibiting effect.
Embodiment 3:
1. experiment process
(1) 8~10 week old C57BL/6J mouse, uses MOG35-55It is immune, mouse is treated since the 25th day, is injected respectively
PBS and carnosol carry out clinical score.
(2) it treats to win respectively for the 60th day and carries out immunohistochemistry and MBP dyeing at PBS and EAE mouse spinal cord lumbosacral enlargement,
And with Imag-Pro quantitative analysis.
(3) proinflammatory (M1) to the macrophage and intrinsic microglia infiltrated in mouse spinal cord and immunological regulation
(M2) marker is dyed, and assesses effect of the carnosol to these cells in spinal cord.
(4) primary microglia is prepared from newborn C57BL/6 mouse, simultaneously with lipopolysaccharides (LPS, 100ng/ml) stimulation
It is handled 2 days with the carnosol of various concentration, the expression of TNF-α in supernatant is detected with ELISA, and collected cell and pass through in real time
The expression quantity of fluorescence quantitative PCR detection related gene.
2. experimental result
Start within (1) the 25th day to treat EAE mouse, it is found that the Disease Clinical Score reduces (p < in carnosol treatment group
0.01-0.001；Figure 12), show that carnosol can improve Remyelination, there are the potentiality for restoring neurotrosis in CNS.
(2) compared with acute stage EAE, in chronic phase (for example, the 60th day, Figure 13 a, Figure 13 b) PBS of EAE and Salvia japonica
The mouse of phenol processing, the inflammatory cell of rare infiltration in white matter, it is the principal pathogenetic of chronic phase EAE that this, which shows neuroinflamation no longer,
Mechanism.
(3) the EAE mouse demyelinate degree of LFB and MBP dyeing display PBS processing is serious, and carnosol processing is small
Demyelinating area substantially reduces in mouse.MBP expression shows that carnosol can be compared to increase before processing after carnosol processing
Inducing remyelination (Figure 13 c- Figure 13 f) to a certain extent.
(4) the 60th days execution EAE mouse, carnosol processing group can be by inhibiting macrophage and intrinsic small colloid thin
The proinflammatory phenotype of born of the same parents simultaneously converts them to immunological regulation phenotype to promote Remyelination (Figure 14).
(5) the primary microglia prepared in new life C57BL/6J mouse, stimulates with LPS and uses the rat-tail of various concentration
Careless phenol processing discovery carnosol effectively inhibits main inflammatory factors the IL-1 β, NOSII and TNF-α of Activated Microglia
Expression (Figure 15).
These results indicate that carnosol can make infiltration macrophage and resident microglia phenotype from it is proinflammatory to
Immunological regulation transformation, to promote remyelination.
Claims (4)
1. application of the carnosol in preparation prevention and treatment experimental autoimmune encephalomyelitis drug.
2. application as described in claim 1, which is characterized in that the structural formula of the carnosol is as follows:
3. application as claimed in claim 1 or 2, which is characterized in that the prevention and treatment experimental autoimmune encephalomyelitis
Drug is the drug for preventing and treating multiple sclerosis, and the drug is by inhibiting CD4+T cell to play it to Th17 cell differentiation
Immune function, while the phosphorylation of STAT3 and NF- κ B needed for inhibiting Th17 cell differentiation.
4. application as claimed in claim 3, which is characterized in that the drug can make the macrophage and intrinsic small glue of infiltration
Cell plastid phenotype is from the proinflammatory M2 Phenotype Transition to immunoloregulation function.
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| CN111686100B (en) * | 2020-06-08 | 2021-08-17 | 重庆医科大学附属第一医院 | Application of CQMU152 in preparing medicament for treating Th17 cell-mediated autoimmune disease |
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| CN103998035A (en) * | 2011-12-19 | 2014-08-20 | 阿雷斯贸易股份有限公司 | Pharmaceutical compositions comprising glitazones and NRF2 activators |
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| CN103998035A (en) * | 2011-12-19 | 2014-08-20 | 阿雷斯贸易股份有限公司 | Pharmaceutical compositions comprising glitazones and NRF2 activators |
Non-Patent Citations (2)
| Title |
|---|
| The Absence of the Pro-antioxidant Transcription Factor Nrf2 Exacerbates Experimental Autoimmune Encephalomyelitis;Delinda A. Johnson et al.;《TOXICOLOGICAL SCIENCES 》;20091112;第114卷(第2期);第237-246页 * |
| upregulation of NF-E2-related factor-2-dependent glutathione by carnosol provokes a cytoprotective response and enhances cell survival;Chien-chung CHEN et al.;《Acta Pharmacologica Sinica》;20101213;第32卷;第62-69页 * |
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