CN106860440A - Application of the fingolimod hydrochloride in systemic lupus erythematosus encephalopathic medicine is prepared - Google Patents
Application of the fingolimod hydrochloride in systemic lupus erythematosus encephalopathic medicine is prepared Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
Abstract
Application of the fingolimod hydrochloride in systemic lupus erythematosus encephalopathic medicine is prepared, fingolimod hydrochloride（FTY720）The behaviouristics symptom of B6.MRL Fas (lpr)/J mouse can be significantly improved, the quantity of Neuron Apoptosis in brain tissue is reduced, mitigates brain tissue inflammation's factor expression level, reduce inflammatory cell infiltration in brain, blood brain barrier integrity can be protected.FTY720 Orally-administrables used of the invention, evident in efficacy, compared with traditional intrathecal injection in treatment mode, administering mode is more convenient, and in the absence of operation risk.
Description
Technical field
The invention belongs to field of medicaments, and in particular to fingolimod hydrochloride is preparing systemic lupus erythematosus encephalopathic medicine
Application in thing.
Background technology
SLE of CNS（neuropsychiatric syndromes of systemic lupus
erythematosus, NP-SLE）It is the complication of SLE most serious, the death rate is higher, is the major causes of death of lupus crisis
One of.The treatment of NP-SLE includes the treatment to protopathy and symptomatic treatment.Treatment to protopathy is typically noted using intrathecal
Penetrate dexamethasone and methotrexate (MTX), although this treatment method can effective relief of symptoms, control the state of an illness of encephalopathic, medication
It is not convenient enough, and as a kind of traumatic treatment means, there is certain operation risk, and be unable to preventive usage.Therefore,
Find it is a kind of equally there is curative effect, but administration is more convenient, and can to a certain degree prevent SLE patient that the medicine gesture of encephalopathic occurs must
OK.Fingolimod hydrochloride FTY720 is a kind of neotype immunosuppressant newfound in recent years, and U.S. FDA approved is used it for
The treatment of multiple sclerosis.Also have been reported that FTY720 has in treatment B6.MRL-Fas (lpr)/J murine lupus nephritis in recent years
It is effective in cure, but its treatment to lupus encephalopathy there is not been reported.
The content of the invention
The technical problem of solution：The present invention provides a kind of fingolimod hydrochloride and is preparing systemic lupus erythematosus encephalopathic
Application in medicine, therapeutic regimens of the FTY720 in terms of B6.MRL-Fas (lpr)/J mice behavior symptoms are improved, can be used for
Systemic lupus erythematosus encephalopathic.
Technical scheme：Fingolimod hydrochloride（FTY720）Answering in systemic lupus erythematosus encephalopathic medicine is prepared
With.
Systemic lupus erythematosus encephalopathic medicine, active ingredient is fingolimod hydrochloride（FTY720）.
Fingolimod hydrochloride（FTY720）Application in prevention system lupus erythematosus brain disease medicine is prepared.
Prevention system lupus erythematosus brain disease medicine, active ingredient is fingolimod hydrochloride（FTY720）.
Beneficial effect：Fingolimod hydrochloride（FTY720）The behaviouristics of B6.MRL-Fas (lpr)/J mouse can be significantly improved
Symptom, reduces the quantity of Neuron Apoptosis in brain tissue, mitigates brain tissue inflammation's factor expression level, reduces inflammatory cell in brain
Infiltration, can protect blood brain barrier integrity.FTY720 Orally-administrables used of the invention, it is evident in efficacy, noted with traditional intrathecal
Penetrate therapeutic modality to compare, administering mode is more convenient, and in the absence of operation risk.
Brief description of the drawings
Fig. 1 be FTY720 B6.MRL-Fas (lpr)/J mouse are ingested, drink water and behaviouristics symptom improvement schematic diagram.
That A figures are represented is the B6.MRL-Fas (lpr)/J mouse food ration reduction, by after FTY720 treatments, ingesting in feeding experiment
Amount is gone up；That B figures are represented is the B6.MRL-Fas (lpr)/J mouse amount of drinking water reduction in experiment of drinking water, and is treated by FTY720
Afterwards, amount of drinking water has gone up；What C figures were represented is the mean dwell time of B6.MRL-Fas (lpr)/J mouse in tail-suspention test
Dramatically increased compared with Normal group, point out it that there is Depression trend, and after FTY720 treatments, the quiescent time of mouse does not treat
Group is substantially reduced；D figures are that in spacious field experiment, total distance of B6.MRL-Fas (lpr)/J spontaneous activity in mice is substantially less than just
Normal control group, points out it to have Depression trend, and after FTY720 treatments, total distance of spontaneous activity in mice is notable compared with non-treatment group
Increase；What E figures were represented is that in spacious field experiment, B6.MRL-Fas (lpr)/J mouse are more normal in total distance of central area activity
Control group increases, abnormal behavior, and after FTY720 treatments, mouse is reduced in the more non-treatment group of total distance of central area activity； F
What figure was represented is that in spacious field experiment, B6.MRL-Fas (lpr)/J mouse are in central area movable total time compared with Normal group
Increase, point out its abnormal behavior, and after FTY720 treatments, mouse is reduced in the total time more non-treatment group of central area activity.
Fig. 2 is that FTY720 reduces cortex, hippocampus and almond nucleus neuron in B6.MRL-Fas (lpr)/J Mice brain tissues
Degeneration apoptosis schematic diagram.What A figures were represented is B6.MRL-Fas (lpr)/J rat corticals, hippocampus and amygdaloid nucleus area nerve
First apoptosis increases, and after FTY720 treatments, Mice brain tissues cortex, hippocampus and amygdaloid nucleus area Neuron Apoptosis are reduced, with
Non- treatment group compares and significantly improves；B figures are cortical area Neuron Apoptosis quantization figures, and C figures are neuron apoptosis in hippocampus quantization figures,
D Tu Shi amygdaloid nucleus area Neuron Apoptosis quantify figure.
Fig. 3 is influence schematic diagrames of the FTY720 to inflammatory factor expression in B6.MRL-Fas (lpr)/J Mice brain tissues.
What A figures were represented is that TNF-α protein level is significantly raised compared with Normal group in B6.MRL-Fas (lpr)/J Mice brain tissues, and
After FTY720 treatments, the more non-treatment group of Mice brain tissues TNF-α protein level substantially reduces；That B figures are represented is B6.MRL-Fas
(lpr) IL-6 protein levels are significantly raised compared with Normal group in/J Mice brain tissues, and after FTY720 treatments, Mice brain tissues
The more non-treatment group of IL-6 protein levels substantially reduces；That C figures are represented is IL-1 β in B6.MRL-Fas (lpr)/J Mice brain tissues
Protein level is significantly raised compared with Normal group, and after FTY720 treatments, the more non-treatment group of Mice brain tissues IL-1 β protein levels
Substantially reduce；What D figures were represented is that TNF-α mRNA level in-site is aobvious compared with Normal group in B6.MRL-Fas (lpr)/J Mice brain tissues
Write and raise, and after FTY720 treatments, the more non-treatment group of Mice brain tissues TNF-α mRNA level in-site substantially reduces；E figure represent be
IL-6 mRNA level in-sites are significantly raised compared with Normal group in B6.MRL-Fas (lpr)/J Mice brain tissues, and FTY720 is treated
Afterwards, the more non-treatment group of Mice brain tissues IL-6 mRNA level in-sites substantially reduces；What F figures were represented is that B6.MRL-Fas (lpr)/J is small
IL-1 β mRNA level in-sites are significantly raised compared with Normal group in murine brain, and after FTY720 treatments, Mice brain tissues IL-1 β
The more non-treatment group of mRNA level in-site substantially reduces.
Fig. 4 is the leaching that FTY720 can substantially reduce neutrophil leucocyte in B6.MRL-Fas (lpr)/J Mice brain tissues
Profit.What A figures were represented is to carry out spy to cortex, hippocampus and almond core region neutrophil leucocyte by myeloperoxidase (MPO)
Opposite sex dyeing；What B figures were represented is B6.MRL-Fas (lpr)/J Mice brain tissues cortical area neutrophilic leukocytosis, and FTY720 is controlled
The infiltration of B6.MRL-Fas (lpr)/J Mice brain tissues cortical area neutrophil leucocyte can be substantially reduced after treatment；C figure represent be
Can be substantially reduced after B6.MRL-Fas (lpr)/J Mice brain tissues hippocampus neutrophilic leukocytosises, FTY720 treatment
The infiltration of B6.MRL-Fas (lpr)/J Mice brain tissues hippocampus neutrophil leucocytes；D figure represent be B6.MRL-Fas (lpr)/
J Mice brain tissues amygdaloid nucleus area neutrophilic leukocytosis, B6.MRL-Fas (lpr)/J mouse brains can be reduced after FTY720 treatments
The infiltration of tissue amygdaloid nucleus area neutrophil leucocyte.
Fig. 5 there is protective effect to show B6.MRL-Fas (lpr)/J Mice brain tissues blood brain barrier integrities for FTY720
It is intended to.What A figures were represented is that the expression of B6.MRL-Fas (lpr)/J Mice brain tissues albumin significantly rises compared with Normal group
Height, after FTY720 treatments, the more non-treatment group of expression of albumin is remarkably decreased；That B figures are represented is B6.MRL-Fas
(lpr)/J Mice brain tissues fibronectin expression levels are significantly raised compared with Normal group, after FTY720 treatments, fibronectin table
Up to level, more non-treatment group is remarkably decreased；What C figures were represented is B6.MRL-Fas (lpr)/J Mice brain tissues matrix metalloproteinases
The expression of MMP2, MMP9 is significantly raised compared with Normal group, and after FTY720 treatments, the expression of MMP2, MMP9 is more not
Treatment group is remarkably decreased；That D figures are represented is B6.MRL-Fas (lpr)/J Mice brain tissues adhesivemoleculeICAM1, VCAM-1
Expression is significantly raised compared with Normal group, and after FTY720 treatments, the more non-treatment group of expression of ICAM-1, VCAM-1 shows
Write and decline.
Specific embodiment
The following examples can make those skilled in the art that the present invention is more fully understood, but limit this never in any form
Invention.
Embodiment 1
FTY720 treatments improve the Behaviors survey of B6.MRL-Fas (lpr)/J mouse
1st, method：Medicine source needed for experiment：FTY720 is purchased from Cayman Chemical companies, and mice behavior experiment is used
Spacious field experiment, tail-suspention test and feeding experiment.The C57BL/6 female mices and B6.MRL-Fas (lpr)/J for taking 8 week old or so are female
Property mouse, is divided into 3 groups：C57BL/6 groups, B6.MRL-Fas (lpr)/J groups, B6.MRL-Fas (lpr)/J+FTY720 groups.Wherein
The medication of B6.MRL-Fas (lpr)/J+FTY720 groups is：Given since B6.MRL-Fas (lpr)/week old of J mouse 8
1mg/kg/day FTY720 gavages, three-times-weekly, remaining two groups are replaced with physiological saline, carried out to 20 weeks or so feeding experiment,
Drinking-water experiment, tail-suspention test and spacious field experiment, experimental result are analyzed with SPSS statistical softwares.
2nd, result：See Fig. 1, after FTY720 treatments, B6.MRL-Fas (lpr)/spontaneous activity of the J mouse in spacious field always away from
From increase, reduced in the distance of central area activity, point out FTY720 to improve the abnormal behaviour disease of B6.MRL-Fas (lpr)/J
Shape；The average dead time is reduced in tail-suspention test, points out FTY720 to improve the depression of B6.MRL-Fas (lpr)/J mouse
Shape.
3rd, step explanation：
Ingest, experiment of drinking water
A. every mouse is individually placed in a mouse cage, and the mouse grain after weighing, drinking water are added to mouse cage.
B. after one week, mouse grain, drinking water are weighed, is recorded on mouse cage label.
Tail-suspention test
A. mouse carries out tail-suspention test in second day after terminating spacious field experiment, is transferred to laboratory endoadaptation environment within 1 hour in advance.
B. rat-tail is connected on experiment frame with adhesive tape, mouse is hung by the feet in sound proof box.
C. activity video recording in mouse 6 minutes is shot using WinFast PVR softwares.
D. the dead time in mouse 6 minutes is recorded a video and counted using TopScanLite software analysis.
Spacious field is tested
A. mouse week old was transferred to laboratory endoadaptation environment in 1 hour in advance at 20 weeks or so.
B. mouse is placed on 20cm long, it is soft using WinFast PVR in the square plastic box of 20cm wide, 35cm high
Part shoots the activity video recording in mouse 6 minutes.
C. mouse total activity distance, activity of the mouse in central area are recorded a video and counted using TopScanLite software analysis
Time and operating range, and mouse enter the number of times of central area.
Embodiment 2
Influences of the FTY720 to Neuron Apoptosis in B6.MRL-Fas (lpr)/J Mice brain tissues
1st, method：Medicine source needed for experiment：Neuron Apoptosis kit Fluoro-Jade B are public purchased from ATT Bioquest
Department.Mouse is grouped as described in embodiment 1, and brain tissue is taken to being put to death at 20 weeks, is carried out Neuron Apoptosis dyeing and is shown in fluorescence
Micro- Microscopic observation（See step explanation）.
2nd, result：See Fig. 2, after FTY720 treatments, although Mice brain tissues neuron apoptosis in hippocampus quantity has been reduced,
But compared with non-treatment group, there were significant differences, and amygdaloid nucleus area Neuron Apoptosis quantity significantly subtracts compared with non-treatment group
It is few.
3rd, step explanation：Fluoro-Jade B are dyeed
A. mouse is anaesthetized in 20 week old, and four limbs are fixed on flat board, opens thoracic cavity, exposes heart, ventricles 300mL
10% formalin（0.1M）Turn white to tissue.
B. brain tissue is taken out, is placed in 10% formalin solution containing 20% sucrose and is fixed overnight.
C., brain tissue is cut into the thin slice of 25 μ m-thicks using freezing microtome.
D. section is dried into half an hour for 50 DEG C with 2% gel embedding on section heater.
E. section is soaked in and places 5 minutes in 80% alcoholic solution containing 1% NaOH, then 70% alcohol 2 minutes,
2 minutes in last distilled water.
F. 0.01% Fluoro-Jade B mother liquors are prepared with distilled water, then with 0.1% peracetic acid formulation 0.0004%
Fluoro-Jade B dyeing liquors.
G. section is placed in dyeing liquor and is dyeed 20 minutes, cleaned with distilled water 3 times, every time 1 minute.
H. section is dried, with fluorescence microscope hippocampus and amygdaloid nucleus area neuron staining situation, shoots and shine
Piece, is quantified with ImageJ softwares to photo.
Embodiment 3
Influences of the FTY720 to inflammatory factor in B6.MRL-Fas (lpr)/J Mice brain tissues
1st, method：Kit source needed for experiment：TNF-α and IL-6 ELISA kits are purchased from U.S. company BD, and mouse is pressed
It is grouped described in embodiment 1, brain tissue is taken during to 20 weeks and is detected for inflammatory factor.To be fixed on flat board after mouse anesthesia,
Thoracic cavity is opened, heart is exposed, ventricles to tissue is carried out with PBS and is turned white, take Mice brain tissues, add 500 μ L PBS, homogenate
12000rpm is centrifuged 5 minutes afterwards, and taking supernatant carries out ELISA experiments.
2nd, result：See Fig. 3, B6.MRL-Fas (lpr)/J Mice brain tissues have inflammatory conditions, in brain tissue TNF-α and
IL-6 levels are significantly raised compared with C57BL/6 mouse, and TNF-α and IL-6 levels are not treated in FTY720 treatment tissues following MCAO in rats
Group is significantly reduced.
3rd, step explanation：
TNF-α level in ELISA method detection brain tissue
A. will capture antibody coating buffer solution by volume 1:250 dilutions, the capture antibody after adding 100 μ L to dilute per hole, envelope
Plate, 4 DEG C of coatings are overnight.Coating buffer is sucked, is washed 3 times with washing lotion, and by plate back-off in blotting residual washing lotion on blotting paper.
B. detect that dilution is closed with least 200 μ L/ holes, be incubated at room temperature 1 hour.Wash 3 times as stated above.
C. 100 μ L standard items, sample and control are added per hole, is incubated at room temperature 2 hours.Wash 5 times as stated above.
D. with detection dilution by volume 1:250 dilution detection antibodies, add the detection after 100 μ L dilutions to resist per hole
Body, is incubated at room temperature 1 hour.Wash 5 times as stated above.
E. with detection dilution by volume 1:250 dilution enzyme reaction things, the enzyme reaction after 100 μ L dilutions is added per hole
Thing, is incubated at room temperature 30 minutes.Wash 7 times as stated above.
F. 100 μ L TMB enzyme substrate solutions are added per hole, room temperature lucifuge is incubated 30 minutes.
G. 50 μ L terminate liquid terminating reactions are added per hole.In 30 minutes at wavelength 450nm read plate.
IL-6 levels in ELISA method detection brain tissue
A. the capture antibody after adding 100 μ L coating buffer solutions to dilute per hole, shrouding, 4 DEG C of coatings are overnight.Coating buffer is sucked,
Washed 3 times with washing lotion, and by plate back-off in blotting residual washing lotion on blotting paper.
B. at least add 200 μ L to detect that dilution is closed per hole, be incubated at room temperature 1 hour.Wash 3 times as stated above.
C. 100 μ L standard items, sample and control are added per hole, is incubated at room temperature 2 hours.Wash 5 times as stated above.
D. 100 μ L operation detection liquid are added per hole（Detection antibody+SAv-HRP）, it is incubated at room temperature 1 hour.As stated above
Washing 7 times.
E. 100 μ L enzyme substrate solutions are added per hole, room temperature lucifuge is incubated 30 minutes.
F. 50 μ L terminate liquid terminating reactions are added per hole.In 30 minutes at wavelength 450nm read plate.
Embodiment 4
FTY720 can substantially reduce the infiltration of neutrophil leucocyte in B6.MRL-Fas (lpr)/J Mice brain tissues
1st, method：Mouse is grouped as described in embodiment 1, to, by mouse anesthesia, ventricle takes brain after being irrigated with 4% formaldehyde at 20 weeks
Tissue is cut into slices, by MPO dye marker neutrophil leucocytes.
2nd, result：See Fig. 4, B6.MRL-Fas (lpr)/J Mice brain tissues have inflammatory conditions, cortex, hippocampus and arteries and veins
In network clump region, it was observed that the neutrophil leucocyte of a large amount of infiltrations, and process B6.MRL-Fas (lpr)/J mouse in FTY720 gavages
In brain tissue cortex, hippocampus and choroid plexus region, it was observed that the neutrophil leucocyte of less infiltration.
Embodiment 5
FTY720 has protective effect to B6.MRL-Fas (lpr)/J blood-brain barrier of mice integralities
1st, method：Mouse is grouped as described in embodiment 1, to, by mouse anesthesia, ventricles PBS removes circulating at 20 weeks
Liquid, takes brain tissue milling and extracting albumen and with albumin level in Western Blot detection Mice brain tissues.
2nd, result：See Fig. 5, B6.MRL-Fas (lpr)/J Mice brain tissues albumin, adhesivemoleculeICAM1, VCAM-1,
The expression of matrix metalloproteinase MMP2, MMP9 is significantly raised compared with Normal group, after FTY720 treatments, above-mentioned albumen
The more non-treatment group of expression is remarkably decreased.
3rd, step explanation：
The expression of albumin in Western Blot methods detection brain, adhesion molecule and matrix metalloproteinase
1) PAGE gel is prepared, resolving gel concentration is 10%, concentration gum concentration is 4%.
2) to fresh electrophoretic buffer is added in inside groove, each sample adds protein 10 μ g, by all samples loading body
Product is adjusted to identical with 1 × sample-loading buffer, is centrifuged in short-term, sample-adding.
3) min of electrophoresis about 30 under 80 V constant voltages, until sample reaches concentration glue bottom and is pressed into herein carefully
Line, then 105V constant voltages electrophoresis to bromophenol blue reach separation gel bottom.
4) pvdf membrane is cut into required size, is positioned in methyl alcohol and soaks 5 min, prepare transferring film buffer solution.
5) electrophoresis terminates, and takes out gel, and filter paper is put well successively according to transferring film " sandwich " order, gel, pvdf membrane, so
It is made transfer folder.
6) in transfer being folded up into transfer device according to correct direction, to pouring into transferring film buffer solution in electrophoresis tank.
7) 2 h or so are transferred under 135 mV constant current conditions.
8) transfer terminates, and pvdf membrane is put into confining liquid, room temperature closing 1-2 h.
9) antibody is diluted with confining liquid according to antibody titer, the hybond membrane after closing is put into hybridization bag, add 1 mL dilute
Primary antibody solution after releasing, sealing machine sealing, mark, 4 DEG C of overnight incubations.
10) primary antibody is incubated and terminates, PBST washings three times, every time 10 min or so.
11) hybond membrane is put into new hybridization bag, adds the two corresponding anti-solution after 1 mL dilutions, be incubated at room temperature 2 hours.
12) PBST is washed three times, 10 min or so every time, the detection of chemiluminescence gel imaging system.
In sum, there is some superiority in FTY720 treatments, what it was administered orally compared with the traditional treatment mode of lupus encephalopathy
Mode greatly facilitates patient, can prevent in the absence of the risk of this traumatic therapeutic modality of intrathecal injection, and early stage administration
The generation of lupus encephalopathy.
Claims (4)
1. fingolimod hydrochloride（FTY720）Application in systemic lupus erythematosus encephalopathic medicine is prepared.
2. systemic lupus erythematosus encephalopathic medicine, active ingredient is fingolimod hydrochloride（FTY720）.
3. fingolimod hydrochloride（FTY720）Application in prevention system lupus erythematosus brain disease medicine is prepared.
4. prevention system lupus erythematosus brain disease medicine, active ingredient is fingolimod hydrochloride（FTY720）.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115281152A (en) * | 2022-08-12 | 2022-11-04 | 浙江中医药大学 | Method for constructing mouse lupus encephalopathy model |
Citations (2)
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| US20090047250A1 (en) * | 2007-08-13 | 2009-02-19 | Elford Howard L | Methods for treating or preventing neuroinflammation or autoimmune diseases |
| CN102209705A (en) * | 2008-11-11 | 2011-10-05 | 诺瓦提斯公司 | Crystalline forms of fingolimod hcl |
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2017
- 2017-01-16 CN CN201710030655.7A patent/CN106860440A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090047250A1 (en) * | 2007-08-13 | 2009-02-19 | Elford Howard L | Methods for treating or preventing neuroinflammation or autoimmune diseases |
| CN102209705A (en) * | 2008-11-11 | 2011-10-05 | 诺瓦提斯公司 | Crystalline forms of fingolimod hcl |
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| Title |
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| DONGYAN SHI等: "FTY720 attenuates behavioral deficits in a murine model of systemic lupus erythematosus", 《BRAIN, BEHAVIOR, AND IMMUNITY》 * |
| HITOAKI OKAZAKI等: "Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus", 《THE JOURNAL OF RHEUMATOLOGY》 * |
| 叶霜等: "FTY720对BXSB小鼠自发性系统性红斑狼疮治疗作用的初步研究", 《中华风湿病学杂志》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115281152A (en) * | 2022-08-12 | 2022-11-04 | 浙江中医药大学 | Method for constructing mouse lupus encephalopathy model |
| CN115281152B (en) * | 2022-08-12 | 2024-03-12 | 浙江中医药大学 | Method for constructing mouse lupus encephalopathy model |
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Application publication date: 20170620 |