CN104606192A - Application of SB202190 in preparation of medicines for treating intractable epilepsy - Google Patents
Application of SB202190 in preparation of medicines for treating intractable epilepsy Download PDFInfo
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- CN104606192A CN104606192A CN201510052375.7A CN201510052375A CN104606192A CN 104606192 A CN104606192 A CN 104606192A CN 201510052375 A CN201510052375 A CN 201510052375A CN 104606192 A CN104606192 A CN 104606192A
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Abstract
The invention relates to application of SB202190 in preparation of medicines for treating intractable epilepsy. By utilizing an intractable epilepsy animal model, due to a series of researches, the SB202190 can reduce the expression of multidrug transporter-P glycoprotein (PGP) related to drug tolerance in the brain of an intractable epilepsy rat, the drug concentration of antiepileptic drugs (AEDs) in hippocampus cell extracellular fluid of the intractable epilepsy rat is improved, the AEDs is assisted to improve the electrophysiological activity of the rat, and the ignition post-attack classification is reduced, namely the drug tolerance of the intractable epilepsy can be improved by the SB202190. The application of the SB202190 is widened, and an effective way is provided for treatment of the intractable epilepsy.
Description
Technical field
The present invention relates to the novelty teabag of SB202190, specifically, relate to the application of SB202190 in the medicine of preparation treatment intractable epilepsy.
Background technology
SB202190 (FHPI, English language Chemical name
4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole) be a kind of effective p38MAPK inhibitor, molecular formula C
20h
14fN
3o, molecular weight 331.3, CAS 152121-30-7.Current in vitro study shows that SB202190 significantly suppresses endogenous background and MAPKAPK 2 activity with anti-Fas antibody induction, and inhibition is dose dependent.SB202190 is inherently enough to the death of inducing Jurkat cell and Hela cell: by activating CPP 32 sample cysteine proteinase, the expression of Bcl-2 capable of blocking.P38 β can alleviate and p 38 alpha can aggravate the apoptosis of being induced by SB202190.In HaCaT cell, SB202190 strong inhibition is by the cox-2 protein expression of ultraviolet induction and mRNA level in-site.With SB202190 process renal cells (normal rat k liver-52E), inflammation (the monocyte chemoattractant protein-1 that can will be caused by albumin, MCP-1) or fibrillation (procollagen I a1, the procollagen-i alpha1) related gene that causes of tumorgrowthfactor-β-1 (TGF β-1) reduce by 50%.SB202190 process A549 cell, can induce JNK phosphorylation (this phosphorylation effect is time and dose dependent), transcription factor ATF-2 phosphorylation, and increase the combination of AP-1 and DNA.SB202190 process promotes the growth of THP-1 and MV4-11 cell.SB202190 can improve c-Raf and ERK (extracellular signal-regulated kinase) phosphorylation, implies the participation of the MAPK path that the Leukemia Cell Proliferation process of being induced by SB202190 has Ras-Raf-MEK-mitogen to activate.In vivo study shows that SB202190 is formed by suppressing p38 to reduce the blister brought out in passive transfer mouse model by people poliomyelitis IgG (PV-IgG).In sepsis endotoxin model, compared with matched group, survival rate can be significantly improved through SB202190 process.
The epileptic of about about 30% is insensitive to antuepileptic (antiepileptic drugs, AEDs), occurs being difficult to controlled recurrent exerbation, is referred to as medically intractable epilepsy.The most outstanding feature of intractable epilepsy be exactly to there being different chemical structures, all kinds of AEDs of different mechanism of action have obvious drug resistance.At present, in zoopery, judge that this drug resistance generally acknowledges that the most responsive, reliable index is After discharge threshold (ADT).Multiple medicines transporter P-glycoprotein (P-glycoprotein, PGP) the intractable epilepsy drug resistance mediated is generally acknowledged (see document 1:Borst p both at home and abroad, Evers R, Kool M, et al.A family of drug transporters:the multidrug resistance-associated proteins [J] .J Natl Cancer Inst.2000,92 (16): 1295-1302.; Document 2:Potschka H, Fedrowitz M, Loscher W.P-glycoproteinand multidrug resistance-associated protein are involved in the regulation ofextracellular levels of the major antiepileptic drug carbamazepine in the brain [J] .Neuroreport.2001,12 (16): 3557-3560.).PGP be find the earliest to participate in the transporter of transport of drug in brain be also study the most widely multiple medicines transporter (see document 1:Lee JC, Laydon JT, McDonnel, et al.A protein kinase involves in the regulation of inflammatorycytokine biosynthesis [J] .Nature.1994,372:739; Document 2:Lavoie JN, Lambert H, Hickey E, et al.Modulation of cellular thermo resistance and actin filament stabilityaccompanies phospharylation induced changes in the oligomeric structure of heatshock protein 27 [J] .Mol Cell Biol.1995,15:505-508.).The transmembrane glycoprotein of PGP to be a kind of molecular weight be 170kD, two identical monomers that complete glycoprotein is made up of 1281 aminoacid are formed, and each monomer all has 6 cross-film districts and 1 adenosine triphosphate (ATP) binding site.Cross-film district is conducive to transport of drug as membrane channels, and ATP binding site is supplied relevant with energy, and this PGP transmembrane structure has the function of energy dependence " Teat pipette ", and medicine and other hydrophobic compound active transport can be gone out cell by it.At human body blood brain barrier position, PGP is positioned on the side of blood capillary hematochezia tube chamber and the outer astroglial foot processes of blood capillary, participates in constituting blood brain barrier.Because it can identify the AEDs of multiple different mechanism of action, initiatively drug efflux pump is gone out blood brain barrier, cause drug level in brain to decline, thus cause drug resistance.
Have not been reported about the effect of SB202190 in treatment intractable epilepsy at present.
Summary of the invention
The object of the invention is, for deficiency of the prior art, to provide the novelty teabag of SB202190.
For achieving the above object, the technical scheme that the present invention takes is:
The application of SB202190 in the medicine of preparation treatment intractable epilepsy.
SB202190 is preparing the application in medicine, and described medicine is for improving or preventing intractable epilepsy to the drug resistance of antuepileptic.
SB202190 is preparing the application in medicine, and described medicine is used for:
A) expression of Hippocampus and cerebral cortex PGP is reduced;
B) drug level of antuepileptic in extracellular fluid of hippocampus is improved; Or
C) epilepsy classification is reduced.
The invention has the advantages that:
This research, on animal models of refractory epilepsy, adopts SABC, impact that Western-blot technical research SB202190 expresses PGP in brain; Employing microdialysis, high-efficient liquid phase chromatogram technology observe the impact of SB202190 on the outer liquid antuepileptic substrate concentration of intractable epilepsy Hippocampal cell; Electrophysiological technique is adopted to observe SB202190 to animal epileptic model electro physiology and ethological impact.Research finds that the PGP that SB202190 can reduce in intractable epilepsy rat brain expresses, improve the drug level of AEDs in the outer liquid of intractable epilepsy Hippocampal cell, AEDs is assisted to improve the bioelectrical activity of drug resistance rat, reduce and light rear outbreak classification, this prompting SB202190 can improve the drug resistance of intractable epilepsy.The present invention has expanded the purposes of SB202190, and the treatment for intractable epilepsy provides a kind of effective way.
Accompanying drawing explanation
The expression of Fig. 1 .PGP in rat brain (fluorescence microscope 400 ×).Indicate: green-PGP, redness-p38, blueness-DAPI; A: Normal group cortex, b:Epilepsy group cortex, c:SB202190 group cortex, d: Normal group Hippocampus, e:Epilepsy group Hippocampus, f:SB202190 group Hippocampus.
The cartogram that Fig. 2 .PGP expresses in rat brain.N group: Normal group, M group: Epilepsy group, S group: SB202190 group.
The expression of Fig. 3 .p38 MAPK and PGP in rat brain.
Fig. 4 .SB202190 is on the impact of Hippocampus of Epileptic Rats extracellular fluid VPA concentration.
Fig. 5 .SB202190 is on the impact of Hippocampus of Epileptic Rats extracellular fluid LTG concentration.
Detailed description of the invention
Below in conjunction with accompanying drawing, detailed description of the invention provided by the invention is elaborated.
1 materials and methods
1.1 experiment materials and equipment
The anti-p38MAPK monoclonal antibody of rabbit: CST company;
Little mouse-anti p-p38 Antibodies Monoclonal antibodies: Santa Cruz company;
Little mouse-anti PGP monoclonal antibody: Abcam company;
Sheep anti-Mouse, goat-anti rabbit DyLight
tMtwo resist: Jackson company;
DAPI, phenytoin Sodium (PHT), sodium valproate, lamotrigine, SB202190:Sigma company;
Microdialysis probe and sleeve pipe: CMA company of Sweden;
CMA/100 micro-injection pump: CMA company of Sweden;
MonEL510 type high performance liquid chromatograph: syltech company of the U.S..
1.2 the foundation of animal epileptic model and grouping
1.2.1 laboratory animal
Laboratory animal selects the male SD rat of 200-250g, totally 60, purchased from BK company.The care of animal and use meet Shanghai City the care of animal committee management regulations.Cleaning grade Animal House, single cage are raised, rest state, and maintenance temperature is 20 ± 2 DEG C, relative humidity is 60%, light application time 12 hours/day, clean drinking-water, feeding standard.
1.2.2 laboratory animal grouping
First laboratory animal is divided into 2 groups at random, is Normal group (Control group) and Epilepsy group respectively.Epileptic rat lumbar injection phenytoin Sodium carries out Drug-resistant screening subsequently.AEDs drug resistance and the responsive group (Sensitive group) of AEDs is divided into according to the selection result.In experiment, AEDs drug resistance rat is divided into two groups more at random, be respectively drug resistance group and (give artificial cerebrospinal fluid in contrast by microdialysis probe, Epilepsy group) and SB202190 group (give SB202190 by microdialysis probe, SB202190group), often at least 8 are organized.
1.2.3 the foundation of drug resistance animal epileptic model
Rat presses 40mg/kg lumbar injection pentetrazole every other day, 14-20 days.Judge whether to light successfully according to or without Epileptic fits.Rat light after convulsant behavior be divided into 6 grades (see document: Souza SC according to the standard of Racine, Palmer HJ, Kang YH, et al.TNF-alpha induction of lipolysis ismediated through activation of the extracellular signal related kinase pathway in3T3-L1adipocytes [J] .J Cell Biochem.2003,89 (6): 1077-1086.).Continuous appearance 3 V level outbreaks, are considered as lighting successfully rat.After determining to light, then After discharge threshold (After dischargethreshold) measure 24h after carry out drug screening, phenytoin Sodium 75mg/kg intraperitoneal injection, after administration, 1h measures ADT after medication.All animals detect 1 time all weekly, repeat totally 3 times.ADT has the range of variation of 20%, therefore the effective mouse standard of PHT is that after each medication, ADT comparatively before increases the rat of 100%; Resistance to PHT light mouse standard for each medication after ADT comparatively before do not increase or only increase 20% rat.
1.3 experimental technique
1.3.1 immunofluorescence
Get cerebral tissue, by brain sheet and mouse monoclonal anti-PGP antibody (1:50) or the anti-p38 antibody (1:50) of rabbit monoclonal 4 DEG C of overnight incubation.By brain sheet and sheep anti-Mouse DyLight
tM(1:500) or goat-anti rabbit DyLight
tM(1:300) 1 hour is hatched for 37 DEG C.After 0.01M PBS rinsing, brain sheet DAPI (1:10000) 37 DEG C is hatched 20min, paster, fluorescence microscope after mounting.Control experiment: replace primary antibodie with normal sheep serum and PBS, synchronously carry out above-mentioned immunofluorescence dyeing, result is negative.Under light microscopic, (100 ×) carry out cell counting to each group of rat brain slice immuning positive cell.Each brain sheet gets 5 visuals field at random at cortex and Hippocampus, asks its arithmetic mean of instantaneous value, and last measurement result all represents with mean+SD.
1.3.2 Western-Blot
Extract Hippocampus and brain cortical tissue, application of sample and electrophoresis, transferring film.After closing, hatched with the anti-p-p38 antibody (1:1000) of mouse monoclonal anti-PGP antibody (1:500) diluted with 5%BSA, rabbit monoclonal anti-p38 antibody (1:1000) and mouse monoclonal respectively by pvdf membrane, 4 DEG C are spent the night.After rinsing, two anti-hatch, and finally develop, take pictures.Using GAPDH as internal reference, equal to prove each histone applied sample amount, represent each histone expression with PGP/GAPDH, p38/GAPDH and p-p38/GAPDH ratio.
1.3.3 microdialysis is set up and the outer liquid acquisition of Hippocampal cell
Each group of rat 10% chloral hydrate (0.4mg/kg) intraperitoneal injection anesthesia, is fixed on stereo brain orienting instrument.Experimentally Hippocampus position determined by zootomy collection of illustrative plates, and coordinate is 3.0mm after bregma, and 2.0mm is opened on side, 3.5mm under cerebral dura mater, connects micro-dialysis device.Micro dialysis needle front end 4mm semipermeable membrane is placed in Hippocampus completely.Micro-perfusion in Graft After pump makes artificial cerebrospinal fluid by inflow pipe, probe, effuser with the constant flow rate of 2.0 μ l/min.Balance 1h, makes the mass exchange of the cerebrospinal fluid in probe and the outer liquid of Hippocampal cell tend towards stability.SB202190 group rat 30min before giving AEDs give SB202190 (4mmol/l) by microdialysis Hippocampus.Each group of rats by intraperitoneal injection sodium valproate 200mg/kg, lamotrigine 10mg/kg, and after administration, 0min, 30min, 60min, 90min, 120min, 150min collect the dialysis solution in effuser after mass exchange, often pipe 20 μ l.-80 DEG C of Refrigerator stores, for efficient Liquid Detection in 2 weeks.Because the permeability of semipermeable membrane is different, the outer response rate of drug level=dialysis solution drug level/probe body of actual extracellular fluid of hippocampus.
1.3.4 the concentration of sodium valproate and lamotrigine in high-performance liquid chromatogram determination dialysis solution
Get dialysis solution sample 20 μ l, directly inject HPLC instrument.Chromatographic condition is: chromatographic column is UltimateXB-C8 packed column (detection sodium valproate), Dikma C18 post (detection lamotrigine), fill particle diameter: 5 μm, 150*4.6mm, mobile phase is methanol: water (55:45) (v:v), flow velocity 1.0ml/min, determined wavelength UV210nm, Detector:L-2400UVD, Column oven:L-2300, Pump:L-2130, column temperature 30 DEG C.
1.3.5 drug resistance rat ADT and ethological mensuration
After pentetrazole is lighted, 24h after appearance 10 grand mal continuously, stimulus intensity is initial from 20 μ A, and increase progressively 20 μ A, the stimulus intervals time is 1min at every turn, until electric discharge after occurring, now current intensity is and lights rear ADT.
Drug resistance group rat gives SB202190 (4mmol/l) by micro dialysis needle Hippocampus, pump in brain through micro-injection pump with the flow velocity of 2.0 μ l/min, and then give 1h after antuepileptic PHT and measure ADT, the classification of observed and recorded two groups of EEG of epileptic rats simultaneously and number of times.
1.4 statistical method
Adopt SPSS11.5 statistical software.Carry out paired t-test or Independent-samples t check analysis between sample, the Behavior evaluation of epileptic rat adopts Kendall Rank correlation.
2 results
2.1 immunofluorescence results
In the expression of all visible PGP of each group of rat hippocampus and cerebral cortex, in Epilepsy group, PGP positive cell number is apparently higher than Normal group, and SB202190 group rat layer and Hippocampus PGP positive cell number are starkly lower than Epilepsy group (P<0.05) (see Fig. 1,2).
2.2 Western-Blot results
After giving SB202190, compared with Epilepsy group, p38, p-p38 and PGP protein expression obviously reduces (P<0.05) (see Fig. 3).
2.3 SB202190 is on the impact of the outer liquid sodium valproate concentration of epileptic rat cortex brain cell
After lumbar injection sodium valproate, 30min can detect sodium valproate in each group of rat dialysis solution.Discovery is compared to the drug level of sodium valproate in each group of each time point dialysis solution: Normal group compares with Epilepsy group, 30min, 60min, 90min and 120min matched group is all higher than Epilepsy group (p value is respectively 0.02,0.01,0.012,0.012), and both 150min no significant difference (p=0.086); SB202190 group compares with Epilepsy group: 30min, 60min, 90min and 120min SB202190 group is all higher than Epilepsy group (p value is respectively 0.02,0.000,0.011,0.028), and both 150min no significant difference (p=0.203).Illustrate that the time-histories of the outer liquid sodium valproate concentration change of Hippocampal cell after giving SB202190 has no change, but add its drug level (see Fig. 4).
2.4 SB202190 is on the impact of the outer liquid lamotrigine concentration of epileptic rat cortex brain cell
After lumbar injection lamotrigine, 30min can detect lamotrigine in each group of rat dialysis solution.Discovery is compared to the drug level of sodium valproate in each group of each time point dialysis solution: Normal group compares with Epilepsy group, 30min, 60min, 90min and 150min Normal group group is all higher than Epilepsy group (p value is respectively 0.02,0.008,0.026,0.02), and both 120min no significant difference (p=0.138); SB202190 group and Epilepsy group: 30min, 60min, 90min, 120min and 150min SB202190 group is all higher than Epilepsy group (p value is respectively 0.017,0.003,0.001,0.004,0.001).Illustrate that the time-histories of the outer liquid lamotrigine concentration change of Hippocampal cell after giving SB202190 has no change, but add its drug level (see Fig. 5).
2.5 SB202190 are on the impact of drug resistance rat ADT
Table 1.SB202190 lights the impact of rear ADT on drug resistance rat
* compared with matched group, p<0.05.
As shown in Table 1, after giving AEDs, the ADT of Sensitive group obviously raises, and increasing degree reaches 105.7%, far away higher than Epilepsy group.Epilepsy group is after giving AEDs, and ADT brings up to 190.0 ± 24.7 by 152.4 ± 33.2, and increasing degree is only 24.7%.And drug resistance epileptic rat is after giving SB202190, ADT brings up to 235.3 ± 52.8 by 167.5 ± 27.9, increases 40.4%.After giving AEDs, SB202190 group ADT is apparently higher than Epilepsy group (P<0.05).Prompting SB202190 improves drug resistance group rat to the drug resistance of AEDs.
2.6 SB202190 are on the ethological impact of drug resistance EEG of epileptic rats
Table 1.SB202190 is on the ethological impact of drug resistance EEG of epileptic rats
* compared with matched group, p<0.05.
As shown in Table 1, find that Epilepsy group lights rear behavior classification all more than III level, III level outbreak appearance 10 times, IV level outbreak appearance 17 times, V level outbreak appearance 18 times, and give SB202190 group and have 2 outbreaks to show as II level, V level is shown effect and has been occurred 12 times, major part outbreak is the outbreak of IV level, and III outbreak is 11 times.Compared with Epilepsy group, the Racine behavior classification of SB202190 group rat obviously declines (p<0.05).
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (3)
- The application of 1.SB202190 in the medicine of preparation treatment intractable epilepsy.
- 2.SB202190, preparing the application in medicine, is characterized in that, described medicine is for improving or preventing intractable epilepsy to the drug resistance of antuepileptic.
- 3.SB202190, preparing the application in medicine, is characterized in that, described medicine is used for:A) expression of Hippocampus and cerebral cortex PGP is reduced;B) drug level of antuepileptic in extracellular fluid of hippocampus is improved; OrC) epilepsy classification is reduced.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108324726A (en) * | 2018-01-29 | 2018-07-27 | 复旦大学附属金山医院 | Applications of the miR-146a in the drug for preparing treatment intractable epilepsy |
| EP3573957A4 (en) * | 2017-01-24 | 2020-11-04 | Rivara, Mirko | Compositions and methods for blocking sodium channels |
-
2015
- 2015-02-02 CN CN201510052375.7A patent/CN104606192A/en active Pending
Non-Patent Citations (4)
| Title |
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| 刘学文等: "p38丝裂原活化蛋白激酶选择性抑制剂对难治性癫痫模型大鼠神经细胞的保护作用及其机制研究", 《中国药房》 * |
| 刘学文等: "SB202190对KA诱导的难治性癫痫大鼠海马神经元的保护作用", 《山东大学学报(医学版)》 * |
| 李熙东等: "SB202190 对卡英酸诱导的癫痫大鼠模型认知功能的影响及机制", 《中山大学学报（医学科学版）》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3573957A4 (en) * | 2017-01-24 | 2020-11-04 | Rivara, Mirko | Compositions and methods for blocking sodium channels |
| US11090289B2 (en) | 2017-01-24 | 2021-08-17 | University Of Virginia Patent Foundation | Compositions and methods for blocking sodium channels |
| CN108324726A (en) * | 2018-01-29 | 2018-07-27 | 复旦大学附属金山医院 | Applications of the miR-146a in the drug for preparing treatment intractable epilepsy |
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