本文選題：實(shí)驗(yàn)性自身免疫性腦脊髓炎 + 苦參素��； 參考：《鄭州大學(xué)》2017年碩士論文

【摘要】：目的:觀察苦參素(Matrine,MAT)對(duì)多發(fā)性硬化癥(multiple sclerosis,MS)經(jīng)典動(dòng)物模型-實(shí)驗(yàn)性自身免疫性腦脊髓炎(experimental autoimmune encephalomyelitis,EAE)急性大鼠模型和慢性進(jìn)行性小鼠的疾病癥狀和病理學(xué)影響,檢測(cè)EAE大鼠體內(nèi)少突膠質(zhì)祖細(xì)胞(OPCs,NG2)增殖與成熟髓鞘細(xì)胞表面標(biāo)志物(MBP)表達(dá)情況,巨噬細(xì)胞/小膠質(zhì)細(xì)胞中炎性M1型CD68+i NOS+與抗炎性M2型CD68+Arg1+的共表達(dá)情況,以及營(yíng)養(yǎng)因子NT3、IGF-1、LIF與JAK2/STAT3信號(hào)傳導(dǎo)通路的變化情況;觀察EAE小鼠脊髓中神經(jīng)營(yíng)養(yǎng)因子NT3的來(lái)源,及NT3+i NOS+和NT3+Arg1+共表達(dá)情況。探究苦參素對(duì)急性期EAE大鼠模型和慢性進(jìn)行性EAE小鼠的巨噬細(xì)胞/小膠質(zhì)細(xì)胞的免疫調(diào)節(jié)作用機(jī)制,旨在為MS患者尋找一種安全、經(jīng)濟(jì)、有效的治療藥物提供實(shí)驗(yàn)依據(jù)。方法:1 1.1建立急性EAE大鼠模型:無(wú)菌配置豚鼠全脊髓勻漿(guinea pig spinal cord homogenate,GPSCH),加入等量弗氏完全佐劑(complete freund adjuvant,CFA,含6mg/ml卡介苗)制成穩(wěn)定油包水型抗原乳劑并免疫誘導(dǎo)6~8周齡雌性Wistar大鼠制備急性模型。1.2大鼠分組與干預(yù):采用隨機(jī)數(shù)字表法將30只免疫后的雌性Wistar大鼠隨機(jī)分為EAE模型組(Vehicle)、MAT預(yù)防組(MAT-P)、MAT治療組(MAT-T),每組10只。同時(shí)選取10只健康雌性Wistar大鼠作為正常組(Normal)。MAT-P組大鼠于免疫后第1天起每日1次給予6.7 ml/kg(250 mg/kg)MAT腹腔注射治療,MAT-T組大鼠在發(fā)病初期(免疫后第11天)起每日1次給予6.7 ml/kg(250 mg/kg)MAT腹腔注射治療,Normal組和Vehicle組大鼠于免疫后第1天起每日1次給予等量生理鹽水替代治療,四組大鼠均干預(yù)至第17天。2 2.1建立慢性進(jìn)行性EAE小鼠模型:采用MOG35-55(10 mg)溶解于2 ml生理鹽水中,與含有2.5 mg/ml結(jié)核分枝桿菌的完全弗氏佐劑等體積混合,使用玻璃注射器將混合液在冰上反復(fù)抽打至完全混合,制成油包水型乳白色乳劑,靜置10min后無(wú)分層為合格。將C57BL/6小鼠使用2%的戊巴比妥麻醉后,在脊柱背側(cè)中線兩側(cè),分四點(diǎn)皮下注射免疫(0.2 ml/只)。在免疫第0天和第2天,每只小鼠分別腹腔注射含200 ng百日咳毒素的PBS溶液,建立EAE小鼠模型。2.2小鼠分組及干預(yù)措施:采用隨機(jī)數(shù)字表法將60只8-10周用MOG35-55免疫后的C57BL/6小鼠分為兩組:EAE模型組(Vehicle)和MAT干預(yù)組(MAT),每組30只。自EAE小鼠發(fā)病初期(免疫后第13天)開(kāi)始給予MAT組小鼠每日1次腹腔注射6.7 ml/kg(200 mg/kg)苦參素注射液,Vehicle組小鼠給予等量生理鹽水替代治療,兩組小鼠均干預(yù)至發(fā)病高峰期(免疫后第22天)。3收集標(biāo)本:在免疫后第18天(大鼠)和23天(小鼠),麻醉動(dòng)物,快速心尖采血取血清后進(jìn)行心臟灌注,收集大小鼠脊髓和腦,部分用4%多聚甲醛固定后制成石蠟切片,其余-80℃凍存?zhèn)溆谩?相關(guān)指標(biāo)檢測(cè):蘇木素-伊紅(Hematoxylin Eosin,HE)染色與Luxol Fast Blue(LFB)染色分別觀察CNS炎性細(xì)胞浸潤(rùn)、髓鞘脫失情況,逆轉(zhuǎn)錄聚合酶鏈反應(yīng)法(RT-PCR法)分析NT3、IGF-1、LIF和JAK2含量,Western Blot法分析Arg-1、i NOS含量,免疫熒光單染學(xué)法分析NT3、MBP表達(dá),免疫熒光雙染分析NG2+PCNA+、CD68+i NOS+、CD68+Arg1+、NG2+NT3+、GFAP+NT3+、CD68+NT3+、NT3+i NOS+、NT3+Arg1+表達(dá),酶聯(lián)免疫吸附法(ELISA法)檢測(cè)STAT3水平。主要研究結(jié)果分為以下三部分第一部分:苦參素對(duì)急性EAE大鼠和慢性進(jìn)行性EAE小鼠臨床癥狀與病理癥狀的影響。1發(fā)病率:Normal組大鼠未觀察到發(fā)病情況,Vehicle組大鼠有9只發(fā)病,發(fā)病率為90%,MAT-T組大鼠有6只發(fā)病,發(fā)病率為60%,MAT-P組有5只發(fā)病,發(fā)病率為50%。Fisher確切概率分析結(jié)果示:Normal組大鼠發(fā)病率顯著低于Vehicle組(p0.01);MAT-T組和MAT-P組大鼠發(fā)病率均明顯低于Vehicle組,差異具有統(tǒng)計(jì)學(xué)意義(p0.05)。此外兩個(gè)MAT組間不存在顯著性差異(p0.05)。Vehicle組小鼠有26只發(fā)病,發(fā)病率86.67%,MAT組小鼠有22只發(fā)病,發(fā)病率73.33%,兩組小鼠發(fā)病率間差異不具有統(tǒng)計(jì)學(xué)意義(p0.05)。2體重變化情況:Normal組大鼠自免疫后第1天起體重平穩(wěn)上升,其余三組大鼠體重整體上均呈先上升后下降趨勢(shì)。MAT-T組和MAT-P組大鼠體重降低幅度均顯著低于Vehicle組大鼠(p0.01)。與MAT-T組大鼠相比,MAT-P組大鼠平均體重變化相對(duì)較小,且有統(tǒng)計(jì)學(xué)差異(p0.05)。EAE小鼠中Vehicle組與MAT組自免疫后平均體重均呈先稍微下降后上升再下降最后上升趨勢(shì),其中MAT組小鼠平均體重降低幅度顯著低于Vehicle組小鼠(p0.01)。3神經(jīng)功能學(xué)評(píng)分:Normal組大鼠平均神經(jīng)評(píng)分一直為0。免疫后第18天,Vehicle組大鼠平均神經(jīng)功能學(xué)評(píng)分顯著高于MAT-T組與MAT-P組大鼠(p0.05)。MAT-T組大鼠神經(jīng)功能評(píng)分顯著高于MAT-P組(p0.05)。EAE小鼠免疫后第23天,Vehicle組小鼠平均神經(jīng)功能學(xué)評(píng)分顯著高于MAT組(p0.05)。4組織病理學(xué)情況:Normal組大鼠平均炎癥浸潤(rùn)評(píng)分、髓鞘脫失評(píng)分和軸索損傷評(píng)分為0,Vehicle組大鼠平均炎癥浸潤(rùn)評(píng)分、髓鞘脫失評(píng)分和軸索損傷評(píng)分較Noraml組明顯升高,差異具有統(tǒng)計(jì)學(xué)意義(p0.01)。MAT-T組平均炎癥浸潤(rùn)評(píng)分、髓鞘脫失評(píng)分和軸索損傷評(píng)分顯著低于Vehicle組(p0.05)。與MAT-T組大鼠相比,MAT-P組大鼠平均炎癥浸潤(rùn)、髓鞘脫失和軸索損傷評(píng)分均進(jìn)一步降低(p0.05)。EAE小鼠中MAT組小鼠平均炎癥浸潤(rùn)評(píng)分和髓鞘脫失評(píng)分均明顯低于Vehicle組,差異具有顯著性意義(p0.01)。第二部分:苦參素對(duì)急性EAE大鼠少突膠質(zhì)祖細(xì)胞增殖、神經(jīng)營(yíng)養(yǎng)因子IGF-1、LIF、NT3和JAK2/STAT3通路的影響。1 EAE大鼠腦組織胼胝體中MBP和NG2+PCNA+的表達(dá):與Normal組相比,Vehicle組MBP和NG2+PCNA+含量顯著性降低(p0.01)。MAT-T組與MAT-P組MBP和NG2+PCNA+表達(dá)均較Vehicle組顯著升高(p0.01),其中MAT-P組MBP和NG2+PCNA+的表達(dá)明顯高于MAT-T組(p0.05)。2脊髓中IGF-1、LIF和NT3含量:Vehicle組較Normal組脊髓中IGF-1、LIF和NT3表達(dá)均顯著降低(p0.01),而兩個(gè)MAT組IGF-1、LIF和NT3表達(dá)水平與Vehicle組相比均呈顯著上升(p0.01),其中MAT-P組上升幅度相對(duì)更加明顯(p0.05)。3大鼠脊髓中JAK2含量與腦組織中STAT3含量:與Normal組相比,Vehicle組大鼠脊髓中JAK2和腦組織中STAT3表達(dá)均顯著升高(p0.01)。兩個(gè)MAT干預(yù)組大鼠JAK2與STAT3水平與Vehicle組相比均呈顯著降低(p0.01),其中MAT-P組大鼠脊髓中JAK2和腦組織中STAT3水平降低幅度顯著大于MAT-T組(p0.05)。第三部分:苦參素對(duì)慢性進(jìn)行性EAE小鼠CNS中神經(jīng)膠質(zhì)細(xì)胞源性NT3和巨噬細(xì)胞/小膠質(zhì)細(xì)胞的影響。1 EAE大鼠腦組織中CD68+i NOS+與CD68+Arg1+共表達(dá)水平:與Normal組相比,Vehicle組大鼠胼胝體中CD68+i NOS+共表達(dá)情況明顯增加,且WB結(jié)果顯示i NOS蛋白含量明顯升高(p0.01)。兩個(gè)MAT干預(yù)組中CD68+i NOS+共表達(dá)情況則明顯降低,且WB結(jié)果顯示i NOS蛋白水平均較Vehicle組顯著性降低(p0.01),其中MAT-P組降低幅度更為明顯(p0.01)。與Normal組相比,Vehicle組大鼠胼胝體中CD68+Arg1+共表達(dá)情況明顯降低,且WB結(jié)果顯示Arg1蛋白含量明顯降低(p0.01)。兩個(gè)MAT干預(yù)組中CD68+i NOS+共表達(dá)情況則明顯升高,且WB結(jié)果顯示Arg1蛋白水平均較Vehicle組顯著性升高(p0.01),其中MAT-P組增加幅度較MAT-T組更為明顯(p0.01)。2 EAE小鼠脊髓組織中NT3、i NOS和Arg1水平:與Vehicle組相比,MAT組小鼠i NOS含量顯著降低(p0.001),而MAT組小鼠Arg1和NT3含量則顯著升高(p0.05,p0.01)。3 EAE大鼠腦組織胼胝體中CD68+i NOS+和CD68+Arg1+共表達(dá)水平:與Normal組相比,Vehicle組大鼠CD68+i NOS+共表達(dá)水平明顯升高(p0.01)。兩個(gè)MAT干預(yù)組CD68+i NOS+共表達(dá)水平均較Vehicle組顯著性降低(p0.01),其中MAT-P組降低幅度更為明顯(p0.01)。Vehicle組較Normal組CD68+Arg1+共表達(dá)水平明顯降低(p0.01)。MAT-T組和MAT-P組CD68+Arg1+共表達(dá)水平均較Vehicle組顯著性增高(p0.01),且MAT-P組較MAT-T組CD68+Arg1+水平高,差異具有統(tǒng)計(jì)學(xué)意義(p0.01)。4 EAE小鼠脊髓中NT3+NG2+、NT3+GFAP+、NT3+CD68+共表達(dá)情況:與Vehicle組相比,MAT組小鼠脊髓中NT3+NG2+、NT3+CD68+、NT3+GFAP+共表達(dá)水平均顯著升高(p0.05,p0.01,p0.001),且NT3+NG2+、NT3+CD68+、NT3+GFAP+共表達(dá)水平增加幅度依次上升。5 EAE小鼠脊髓中NT3+i NOS+和NT3+Arg1+共表達(dá)情況:與Vehicle組相比,MAT組脊髓中NT3+i NOS+表達(dá)明顯降低(p0.01),而MAT組脊髓中NT3+Arg1+共表達(dá)則顯著升高(p0.001)。結(jié)論MAT對(duì)急性EAE大鼠和慢性進(jìn)行性EAE小鼠具有良好的防治作用,可能是通過(guò)下調(diào)JAK2/STAT3通路的表達(dá),上調(diào)神經(jīng)膠質(zhì)細(xì)胞中神經(jīng)營(yíng)養(yǎng)因子NT3的分泌,促進(jìn)巨噬細(xì)胞和小膠質(zhì)細(xì)胞由促炎性M1型向抗炎性M2型的轉(zhuǎn)化,提高神經(jīng)元生存微環(huán)境,從對(duì)急性EAE大鼠和慢性進(jìn)行性EAE小鼠起到良好的防治效果。
[Abstract]:Objective: To observe the effects of Matrine (MAT) on the classical animal model of multiple sclerosis (multiple sclerosis, MS) - experimental autoimmune encephalomyelitis (experimental autoimmune encephalomyelitis, EAE) acute rat model and chronic progressive mice, the pathological and pathological effects of the disease, and the detection of oligodendrocyte progenitor cells in EAE rats. (OPCs, NG2) the expression of the proliferation and mature myelin cell surface markers (MBP), the co expression of inflammatory M1 CD68+i NOS+ and anti inflammatory M2 CD68+Arg1+ in macrophage / microglia, and the alteration of the nutritional factors NT3, IGF-1, LIF and JAK2/STAT3 signal transduction pathways. Source, NT3+i NOS+ and NT3+Arg1+ co expression. To explore the immunomodulatory mechanism of Matrine on acute phase EAE rat model and chronic progressive EAE mouse macrophage / microglia, and to provide a basis for finding a safe, economical and effective therapeutic drug for MS patients. Methods: 11.1 an acute EAE rat model was established. Guinea pig spinal cord homogenate (GPSCH) was added to the whole spinal cord of guinea pigs. The stable oil coated water antigen emulsion was prepared by adding the equivalent Freund complete adjuvant (complete Freund adjuvant, CFA, 6mg/ml BCG) and immunized to induce the acute model of female rats with 6~8 weeks. 30 female Wistar rats were randomly divided into EAE model group (Vehicle), MAT prevention group (MAT-P), MAT treatment group (MAT-T) and 10 rats in each group. At the same time, 10 healthy female Wistar rats were selected as normal group (Normal).MAT-P group, and 6.7 ml/kg (250 mg/kg) were given 1 times a day after first days of immunization. At the initial stage (eleventh days after immunization), 6.7 ml/kg (250 mg/kg) MAT were given 1 times a day for intraperitoneal injection, and the rats in group Normal and Vehicle were given equal amount of saline replacement therapy for 1 times a day after first days of immunity. The four groups of rats were intervened to establish a chronic progressive EAE mouse model at seventeenth days, with MOG35-55 (10 mg) dissolved in 2. In ml normal saline, mixed with a complete Freund's adjuvant containing 2.5 mg/ml Mycobacterium tuberculosis, a glass syringe was used to beat the mixture into a complete mixture on the ice to make the oil water milk white emulsion. After the static 10min, no stratification was qualified. The C57BL/6 mice were anesthetized with 2% pentobarbital and in the dorsal midline of the spine. On both sides, immunization (0.2 ml/) was subcutaneously injected at four points. In the zeroth and second days of immunization, each mouse was intraperitoneally injected with PBS solution containing 200 ng pertussis toxin, and the.2.2 mice of the EAE mouse model were divided into groups and intervention measures: the 60 8-10 weeks C57BL/6 mice immunized with MOG35-55 were divided into two groups: EAE model group (Vehi). CLE) and MAT intervention group (MAT), 30 in each group. From the early onset of EAE mice (thirteenth days after immunization), the MAT group mice were given 6.7 ml/kg (200 mg/kg) Marine Injection every day. The Vehicle mice were given the equivalent saline replacement therapy. The two groups were all intervened to the peak period of the onset (twenty-second days after immunization). Eighteenth days after the epidemic (rats) and 23 days (mice), the anaesthetized animals, the rapid apex blood sampling to take the blood serum for heart perfusion, collecting the spinal cord and brain of the rats, partially fixed with 4% polyformaldehyde to make paraffin sections, and the remaining -80 degrees centigrade for.4 Related Indexes Detection: hematoxylin Yi Hong (Hematoxylin Eosin, HE) staining and Luxol Fast Blue (LFB) staining The infiltration of inflammatory cells and the loss of myelin sheath were observed, and the contents of NT3, IGF-1, LIF and JAK2 were analyzed by reverse transcription polymerase chain reaction (RT-PCR). Western Blot method was used to analyze Arg-1, I NOS content, immunofluorescence staining and immunofluorescence analysis. +i NOS+, NT3+Arg1+ expression, enzyme linked immunosorbent assay (ELISA method) detection of STAT3 level. The main results are divided into the following three parts: the first part of the study: the effect of Matrine on the clinical symptoms and pathological symptoms of acute EAE rats and chronic progressive EAE mice, the incidence of.1: the Normal group was not observed, and there were 9 rats in the Vehicle group. The incidence was 90% in group MAT-T, 6 in group MAT-T and 5 in group MAT-P. The incidence of the incidence was 50%.Fisher exact probability analysis. The incidence of Normal rats was significantly lower than that in Vehicle group (P0.01); the incidence of MAT-T and MAT-P rats was significantly lower than that in group Vehicle (P0.05). In addition, two MAT groups There was no significant difference (P0.05) between 26 mice in group.Vehicle and 86.67% of the incidence, 22 in MAT group and 73.33% in the incidence rate of the two groups. The difference between the two groups was not statistically significant (P0.05), the body weight of the Normal group increased steadily from the day of the immunization, and the body weight of the other three groups was all on the whole. The weight decrease of.MAT-T group and MAT-P group was significantly lower than that of group Vehicle (P0.01). Compared with the MAT-T group, the average weight of the MAT-P group was relatively small, and there was a statistically significant difference (P0.05) the average weight of Vehicle group and MAT group in.EAE mice was slightly decreased and then increased then. The average weight reduction of group MAT mice was significantly lower than that in group Vehicle (P0.01).3 neurologic score: the average nerve score of group Normal was 0. after eighteenth days, and the average neurologic score of group Vehicle was significantly higher than that in group MAT-T and MAT-P group rats (P0.05).MAT-T group. The score was significantly higher than that in group MAT-P (P0.05).EAE mice twenty-third days after immunization. The average neurologic score of group Vehicle mice was significantly higher than that in group MAT (P0.05).4 histopathology: the average inflammatory infiltration score, the myelin loss score and the axonal injury score in the Normal group were 0, the average inflammatory infiltration score in the group Vehicle, the myelin loss score and the score of the myelin sheath, and the score of the myelin loss and the loss of myelin. The score of axonal injury was significantly higher than that in the Noraml group. The difference was statistically significant (P0.01) the average inflammatory infiltration score in the group.MAT-T, the myelin loss score and the axonal injury score were significantly lower than that of the Vehicle group (P0.05). Compared with the MAT-T group, the average inflammatory infiltration in the group of MAT-P rats, the myelin loss and axonal injury scores were further reduced (P0.05).EAE The average inflammatory infiltration score and the myelin loss score in the MAT group were significantly lower than that in the Vehicle group, and the difference was significant (P0.01). The second part: the effect of Matrine on oligodendrocyte progenitor cell proliferation in acute EAE rats, the effects of neurotrophic factor IGF-1, LIF, NT3 and JAK2/STAT3 pathway on MBP and NG2+PC in the corpus callosum of.1 EAE rat brain tissue The expression of NA+: compared with group Normal, the content of MBP and NG2+PCNA+ in group Vehicle decreased significantly (P0.01), the expression of MBP and NG2+PCNA+ in.MAT-T group and MAT-P group was significantly higher than that in Vehicle group (P0.01). The expression of F and NT3 decreased significantly (P0.01), while the expression level of IGF-1, LIF and NT3 in the two MAT groups was significantly higher than that of the Vehicle group (P0.01), and the increasing amplitude of the MAT-P group was more obvious (P0.05) in the spinal cord of the.3 rats and the content of the brain tissue. The levels of JAK2 and STAT3 in the two MAT intervention groups were significantly lower than those in the Vehicle group (P0.01). The decrease of STAT3 level in the JAK2 and brain tissues in the spinal cord of the MAT-P group was significantly greater than that in the MAT-T group (P0.05). The third part: the neuroglial cells derived from the chronic progressive EAE mice and in the chronic progressive EAE mice. The effect of macrophage / microglia on the co expression of CD68+i NOS+ and CD68+Arg1+ in the brain tissue of.1 EAE rats: compared with the Normal group, the co expression of CD68+i NOS+ in the corpus callosum of the Vehicle group was significantly increased, and the WB results showed a significant increase in the I NOS protein content. The co expression of the CD68+i was obvious in the two intervention groups. The WB results showed that the level of I NOS protein was significantly lower than that of the Vehicle group (P0.01), and the decrease in MAT-P group was more obvious (P0.01). The co expression of CD68+Arg1+ in the corpus callosum in the Vehicle group was significantly lower than that in the Normal group, and the WB results showed that the Arg1 protein content was significantly reduced. The WB results showed that the level of Arg1 protein was significantly higher than that in the Vehicle group (P0.01), and the increase in the MAT-P group was more obvious than that in the MAT-T group (P0.01) in the spinal cord of.2 EAE mice. The level of co expression of CD68+i NOS+ and CD68+Arg1+ in the corpus callosum of.3 EAE rats was significantly increased (P0.05, P0.01). The level of CD68+i NOS+ co expression in the Vehicle group was significantly higher than that in the Normal group (P0.01). The level of co expression in the two intervention groups was significantly lower than that of the Normal group. The co expression level of CD68+Arg1+ in group Normal was significantly lower than that of group Normal (P0.01) in group.Vehicle (P0.01), and CD68+Arg1+ co expression level in group.MAT-T and MAT-P group was significantly higher than that in group Vehicle (P0.01), and MAT-P group was higher than that of MAT-T group. As compared with the Vehicle group, the co expression level of NT3+NG2+, NT3+CD68+ and NT3+GFAP+ in the spinal cord of group MAT mice increased significantly (P0.05, P0.01, p0.001), and the increase of NT3+NG2+, NT3+CD68+, NT3+GFAP+ co expression level in the spinal cord of the mice was increased in turn. The expression of NOS+ was significantly decreased (P0.01), while the co expression of NT3+Arg1+ in the spinal cord of MAT group was significantly increased (p0.001). Conclusion MAT has a good preventive effect on acute EAE rats and chronic progressive EAE mice. It may be through down regulation of the expression of JAK2/STAT3 pathway, up regulation of the secretion of neurotrophic factor NT3 in glial fine cells, and promoting macrophage and macrophage. The transformation of microglia from proinflammatory M1 type to anti inflammatory M2 type improves the survival microenvironment of neurons, and has a good effect on the prevention and treatment of acute EAE rats and chronic progressive EAE mice.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R285.5

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