【摘要】：由神經(jīng)細(xì)胞增殖、遷移、分化異常所導(dǎo)致的皮質(zhì)發(fā)育障礙(Malformation of cortical development,MCD)是癲癇形成的重要病理生理基礎(chǔ),而且是導(dǎo)致其藥物難以控制的重要原因之一。近年來隨著高清影像學(xué)技術(shù)的普及,MCD的臨床檢出率不斷提高,為進(jìn)一步研究癲癇提供了重要的臨床條件,也使得這一疾病日益成為癲癇領(lǐng)域最活躍的研究熱點(diǎn)之一,故而對MCD的發(fā)生及致癇機(jī)制的研究將會推進(jìn)對藥物難治性癲癇發(fā)病機(jī)制的新認(rèn)識及防治策略的革新,并且對改善癲癇患者生存質(zhì)量有重要現(xiàn)實意義。MCD的最常見的臨床分型包括局灶性皮質(zhì)發(fā)育不良(FCD)及結(jié)節(jié)性硬化(TSC)。其典型病理學(xué)特征是皮層板層結(jié)構(gòu)紊亂、病灶內(nèi)出現(xiàn)異常發(fā)育的異構(gòu)神經(jīng)元如氣球樣細(xì)胞(Balloon cells,BC)、異形神經(jīng)元(Dysmorphic neuron,DN),巨大神經(jīng)元(Giant neuron,GN)等。我們及其他學(xué)者的臨床研究顯示具有異形神經(jīng)元的FCD II型(皮層結(jié)構(gòu)紊亂+異構(gòu)神經(jīng)元)較I型(僅有皮層結(jié)構(gòu)紊亂)患者癲癇發(fā)病年齡更早、發(fā)作頻率更高、發(fā)作程度更嚴(yán)重、藥物難治性比例更高。但MCD的致癇機(jī)制十分復(fù)雜,至今尚不完全清楚,隨著近年研究的深入,無菌性炎癥與癲癇的關(guān)系越來越受到關(guān)注,炎癥相關(guān)的異常電活動在癲癇的發(fā)生、發(fā)展及預(yù)后中所起的關(guān)鍵作用。深入研究炎癥信號在MCD致癇灶中的作用,將有助于人們進(jìn)一步認(rèn)識和闡明MCD的致癇機(jī)制。在本研究中,我們以MCD臨床手術(shù)切除的標(biāo)本為研究對象,并建立了MCD動物模型,初步研究了FCD和TSC皮層病灶以及動物模型中P2X7R-Caspase1-IL1β信號系統(tǒng)的表達(dá)分布,分析了P2X7R及其介導(dǎo)的炎癥信號系統(tǒng)在致癇灶中的潛在作用。主要結(jié)果如下:一、嘌呤能離子通道受體7(Purinergic ligand-gated ion channel 7 receptor,P2X7R)在MCD患者大腦皮層中的表達(dá)分布1.應(yīng)用Real-time PCR及Western blot技術(shù),我們評價了P2X7R m RNA及蛋白在CTX及FCD臨床標(biāo)本中的表達(dá)情況。結(jié)果顯示,P2X7R的m RNA水平高于正常對照CTX(P0.05);在FCD各個亞型中,FCD IIa和FCD IIb型的m RNA水平明顯高于FCD Ia,差異有統(tǒng)計學(xué)意義(P0.05),而FCD IIa和FCD IIb的P2X7R m RNA表達(dá)水平差異未見統(tǒng)計學(xué)意義;Western-blot檢測P2X7R結(jié)果同樣顯示,在臨床FCD標(biāo)本中,P2X7R的蛋白水平明顯高于CTX正常對照(P0.05),并且FCDII型中的蛋白水平明顯高于FCD Ia(P0.05)。2.利用免疫組化及熒光雙標(biāo)技術(shù),我們進(jìn)一步分析了P2X7R在CTX和FCD組織中的定位情況,免疫組化顯示,P2X7R在CTX標(biāo)本中蛋白表達(dá)呈弱陽性,在灰質(zhì)區(qū)域主要表達(dá)在神經(jīng)細(xì)胞中,而在白質(zhì)區(qū)域,可于少量膠質(zhì)細(xì)胞樣細(xì)胞上呈較弱表達(dá);在FCD Ia組織中,P2X7R呈現(xiàn)出中到強(qiáng)表達(dá)于灰質(zhì)及灰、白質(zhì)交界區(qū)的微柱狀排列的肥大神經(jīng)細(xì)胞中,也表達(dá)于灰、白質(zhì)交界區(qū)的部分膠質(zhì)細(xì)胞樣細(xì)胞中;而在FCD IIa和FCD IIb標(biāo)本中,P2X7R強(qiáng)表達(dá)于75%±5.6%的DN和64%±6.7%的BC中。并且值得注意的是,在FCD標(biāo)本中,細(xì)胞大小、形態(tài)大致正常的神經(jīng)元中,P2X7R的表達(dá)也明顯高于CTX組。免疫熒光雙標(biāo)結(jié)果顯示,在FCD標(biāo)本中,P2X7R表現(xiàn)出較強(qiáng)的免疫活性,在異形神經(jīng)元(dysmorphic neuron,DN)和氣球樣細(xì)胞(Balloon cell,BC)中均有表達(dá),與神經(jīng)元標(biāo)志物Neu N共標(biāo),同時與大部分(80%)活化的星形膠質(zhì)細(xì)胞(GFAP)和小膠質(zhì)細(xì)胞(HLA)共標(biāo)。3.我們同時評價了P2X7R m RNA及蛋白在TSC臨床標(biāo)本致癇結(jié)節(jié)中的表達(dá)情況,結(jié)果顯示,P2X7R的m RNA水平較正常對照CTX顯著增高,其差異有統(tǒng)計學(xué)意義(P0.05);Western-blot檢測P2X7R結(jié)果同樣顯示,在臨床TSC標(biāo)本中,P2X7R的蛋白水平明顯高于CTX正常對照(P0.05)。免疫組化結(jié)果中,相對于CTX標(biāo)本,P2X7R在TSC標(biāo)本中強(qiáng)表達(dá)于超過90%的DN中;免疫熒光雙標(biāo)結(jié)果顯示,在TSC標(biāo)本中,P2X7R強(qiáng)表達(dá)于異形神經(jīng)元細(xì)胞中(DN,BC,GN),其免疫陽性細(xì)胞可與神經(jīng)元標(biāo)志物NF200和星形膠質(zhì)細(xì)胞GFAP共標(biāo)。二、IL-1β及其受體在FCD中的表達(dá)分布對臨床FCD標(biāo)本的研究顯示,IL-1β/IL-1R1的m RNA水平高于正常對照CTX(P0.05);在FCD各個亞型中,FCD IIa和FCD IIb型的IL-1β/IL-1R1 m RNA水平明顯高于FCD Ia(P0.05),而在FCD IIa和FCD IIb的比較中,二者m RNA水平差異未見統(tǒng)計學(xué)意義;Western-blot檢測IL-1β/IL-1R1結(jié)果同樣顯示,在臨床FCD標(biāo)本中,IL-1β/IL-1R1二者的蛋白水平明顯高于CTX正常對照(P0.05),并且FCDII型中的蛋白水平明顯高于FCD Ia(P0.05)。免疫組化顯示,IL-1β及IL-1R1在CTX標(biāo)本中免疫組化染色呈弱陽性,主要在神經(jīng)元樣細(xì)胞和少量星形膠質(zhì)細(xì)胞樣細(xì)胞上發(fā)現(xiàn)較弱表達(dá);在FCD Ia組織中,IL-1β/IL-1R1呈現(xiàn)出中到強(qiáng)表達(dá)于灰質(zhì)及灰、白質(zhì)交界區(qū)的微柱狀排列的肥大神經(jīng)細(xì)胞中,也表達(dá)于灰、白質(zhì)交界區(qū)的部分星形膠質(zhì)細(xì)胞樣細(xì)胞中;而在FCD IIa和FCD IIb標(biāo)本中,IL-1β強(qiáng)表達(dá)于89%±6.2%的DN(n=650)和84%±5.7%的BC(n=255)中。免疫熒光雙標(biāo)結(jié)果顯示,在FCD標(biāo)本中,IL-1β/IL-1R1表現(xiàn)出較強(qiáng)的免疫活性,表達(dá)在異形神經(jīng)元DN和BC,與神經(jīng)元標(biāo)志物Neu N共標(biāo),同時與大部分(80%)活化的星形膠質(zhì)細(xì)胞(GFAP)和小膠質(zhì)細(xì)胞(HLA)共標(biāo),此表達(dá)分布與P2X7R類似。三、P2X7受體在烷基化物甲基偶氮甲醇(methylazoxymethanol acetate,MAM)模型中的表達(dá)及蛋白分布1.MCD模型大鼠皮質(zhì)發(fā)育障礙模型基本特點(diǎn)我們應(yīng)用烷基化物甲基偶氮甲醇(methylazoxymethanol acetate,MAM)給予孕鼠腹腔注射,誘導(dǎo)仔鼠出現(xiàn)類似臨床病理改變的皮質(zhì)發(fā)育障礙,從而對MCD進(jìn)行動物模擬。結(jié)果提示MAM大鼠皮質(zhì)發(fā)育障礙動物模型,仔鼠出現(xiàn)小頭畸形,自主活動減少,對外界刺激反應(yīng)較遲鈍,爬行及躲避性動作靈活性下降,攝食能力下降,體重減輕,主要病理表現(xiàn)為腦皮質(zhì)變薄,板層結(jié)構(gòu)不清,細(xì)胞排列紊亂,神經(jīng)元形態(tài)異常,神經(jīng)元胞體增大,正常極性消失,于分子層可見眾多異位的神經(jīng)元,呈團(tuán)塊樣聚集,并可見病理性結(jié)節(jié),具有FCDII型的病理改變;2.P2X7受體m RNA在CTX及MAM大鼠MCD模型皮層中的表達(dá)情況應(yīng)用Real-time PCR、免疫組化方法,對MAM大鼠皮質(zhì)發(fā)育障礙模型和正常對照進(jìn)行了研究,結(jié)果發(fā)現(xiàn),在MAM皮質(zhì)發(fā)育障礙模型不同年齡段(2,4,6周)大鼠標(biāo)本中,同年齡段組內(nèi)比較,P2X7 m RNA在MAM皮質(zhì)發(fā)育障礙大鼠皮層中表達(dá)明顯高于正常對照組(CTX);應(yīng)用免疫組化方法對比了P2X7R、Caspase-1、IL-1β在MAM模型大鼠腦組織中的表達(dá)分布,結(jié)果顯示P2X7R在大鼠CTX正常對照標(biāo)本中呈弱到中等強(qiáng)度表達(dá),但僅分布在少量(22.9%±3.4%,n=379)的神經(jīng)元樣細(xì)胞中、膠質(zhì)細(xì)胞樣細(xì)胞上發(fā)現(xiàn)較弱表達(dá);而在MAM皮質(zhì)發(fā)育障礙組織中,皮層細(xì)胞排列紊亂,P2X7R中到強(qiáng)表達(dá)并廣泛分布于灰質(zhì)及灰、白質(zhì)交界區(qū)中排列紊亂、形態(tài)異常的“異形神經(jīng)元”和星形膠質(zhì)細(xì)胞中;同樣IL-1β、Caspase-1在MAM皮質(zhì)發(fā)育障礙大鼠皮層中的m RNA及蛋白表達(dá)明顯高于CTX正常對照標(biāo)本;MAM皮質(zhì)發(fā)育障礙模型大鼠的IL-1β表達(dá)強(qiáng)度及免疫陽性細(xì)胞數(shù)量明顯高于對照組。結(jié)論如下:1.我們首次從m RNA和蛋白水平分析了P2X7R在CTX和FCD中的表達(dá)情況。結(jié)果顯示,FCD患者P2X7R的m RNA及蛋白表達(dá)顯著高于正常對照CTX;FCD IIa和FCD IIb的m RNA及蛋白水平明顯高于FCD Ia。并且在FCD Ia組織中,P2X7R強(qiáng)表達(dá)于灰質(zhì)及灰、白質(zhì)交界區(qū)的微柱狀排列的肥大神經(jīng)細(xì)胞,也表達(dá)于灰、白質(zhì)交界區(qū)的部分膠質(zhì)細(xì)胞樣細(xì)胞中;而在FCD IIa和FCD IIb標(biāo)本中,P2X7R強(qiáng)表達(dá)于DN和BC中,與神經(jīng)元標(biāo)志物Neu N共標(biāo),同時與大部分(80%)活化的星形膠質(zhì)細(xì)胞(GFAP)和小膠質(zhì)細(xì)胞(HLA)共標(biāo)。2.TSC患者致癇灶中P2X7R m RNA及蛋白表達(dá)顯著高于對照組,并且相對于CTX標(biāo)本,P2X7R在TSC標(biāo)本中強(qiáng)表達(dá)于超過90%的DN中;與神經(jīng)元標(biāo)志物NF200及星形膠質(zhì)細(xì)胞標(biāo)志物GFAP共標(biāo)。3.在FCD患者致癇灶內(nèi),IL-1β及其受體IL-1R1及Caspase-1 m RNA及蛋白表達(dá)均顯著高于正常對照組。4.最后我們采用孕鼠腹腔注射MAM誘導(dǎo)MCD動物模型的方法,初步驗證了P2X7R對癲癇發(fā)作的作用,結(jié)果顯示P2X7R激動劑Bz ATP可以使癲癇發(fā)作時間明顯提前,易化了匹魯卡品誘導(dǎo)的癲癇發(fā)作。綜合上述結(jié)果,我們推斷:P2X7R及其介導(dǎo)的Caspase1-I/L1β信號通路,在MCD癲癇發(fā)作的過程中發(fā)揮重要致癇作用。
[Abstract]:Cortical dysplasia (Malformation of cortical development, MCD), which is caused by the proliferation, migration and differentiation of nerve cells, is an important pathophysiological basis for the formation of epilepsy, and is one of the important reasons for the difficult control of its drugs. In recent years, with the popularization of high definition imaging technology, the clinical detection rate of MCD has been continuously improved. The further study of epilepsy provides important clinical conditions and makes the disease one of the most active research hot spots in the field of epilepsy. Therefore, the study of the pathogenesis of MCD and the mechanism of epilepsy will promote the new understanding of the mechanism of drug refractory epilepsy and the innovation of the prevention and treatment strategies, and improve the quality of life of the epileptic patients. The most common clinical types of important practical.MCD include focal cortical dysplasia (FCD) and nodular sclerosis (TSC). The typical pathological features are the disorder of the cortical lamellar structure, and the abnormal development of the isomerism neurons such as the Balloon cells (BC), the heteromorphic neurons (Dysmorphic neuron, DN), and the giant nerve. Giant neuron, GN, et al. Our and other scholars' clinical studies show that FCD II (cortical disorder + isomeric neurons) with heteromorphic neurons (cortical structural disorders + isomeric neurons) are older than those of the I type (only cortical disorders), with more frequent episodes, more severe episodes and higher drug refractory proportions. But the mechanism of MCD is very complex. The relationship between aseptic inflammation and epilepsy is becoming more and more concerned with recent research. The key role of abnormal electrical activity related to inflammation in the occurrence, development and prognosis of epilepsy. The in-depth study of the role of inflammatory signals in MCD epileptic foci will help people to further understand and clarify MCD In this study, in this study, we studied the specimens removed by MCD and established the MCD animal model. We preliminarily studied the expression and distribution of the P2X7R-Caspase1-IL1 beta signal system in the FCD and TSC cortical lesions and the animal models, and analyzed the potential role of P2X7R and its mediated inflammatory signal system in the epileptic foci. The main results are as follows: (1) the expression distribution of the purine energy ion channel receptor 7 (Purinergic ligand-gated ion channel 7 receptor, P2X7R) in the cerebral cortex of the MCD patients 1. application of Real-time PCR and Western blot technique. The level of M RNA in FCD IIa and FCD IIb was significantly higher than that of FCD Ia in the FCD subtypes of FCD, and there was no significant difference in the level of M RNA in FCD IIa and FCD IIb. The protein level in FCDII was significantly higher than that of CTX (P0.05), and the protein level in FCDII was significantly higher than that of FCD Ia (P0.05).2. using immunohistochemistry and fluorescence double labeling technique. We further analyzed the localization of P2X7R in CTX and FCD tissues. Immunohistochemistry showed that P2X7R protein expression in the CTX specimens was weakly positive, and the main expression in the gray matter region was in the deity. In the cells, in the white matter region, it can be weakly expressed on a small number of glial cell like cells; in FCD Ia tissue, P2X7R appears to be strongly expressed in gray matter and ash, and in the microcolumnar hypertrophic neurons of the white matter junction, also in some glial cell like cells of the gray matter and the white matter junction; and in the FCD IIa and FCD IIb standard. In this case, P2X7R was strongly expressed in 75% + 5.6% DN and 64% + 6.7% BC. And it is worth noting that in the FCD specimens, the expression of P2X7R was significantly higher than that in the CTX group. The results of immunofluorescence double labeling showed that P2X7R showed strong immune activity in the FCD specimens, and in the heteromorphic neurons (dysmorphic neu). Ron, DN) and balloon like cells (Balloon cell, BC) were expressed, CO labeled with the neuronal marker Neu N, and co labeled with most (80%) activated astrocytes (GFAP) and microglia (HLA). We also evaluated the expression of P2X7R m and protein in the epileptic nodules on the bed specimens. Compared with normal control CTX, the difference was statistically significant (P0.05); Western-blot test P2X7R results also showed that in the clinical TSC specimens, the protein level of P2X7R was significantly higher than that of the normal CTX control (P0.05). In the immunohistochemical results, the P2X7R in the TSC specimen was strongly expressed in more than 90% of the DN; double immunofluorescent labeling. The results showed that in the TSC specimens, P2X7R was strongly expressed in the heteromorphic neurons (DN, BC, GN), and the immunoreactive cells were co labeled with the neuronal marker NF200 and astrocyte GFAP. Two, the expression distribution of IL-1 beta and its receptor in FCD showed that the IL-1 beta /IL-1R1 was higher than the normal control. In the various subtypes of FCD, the IL-1 beta /IL-1R1 m RNA levels of FCD IIa and FCD IIb were significantly higher than FCD Ia (P0.05). Normal control (P0.05), and the protein level in type FCDII was significantly higher than that of FCD Ia (P0.05). Immunohistochemical staining showed that IL-1 beta and IL-1R1 were weakly positive in immunohistochemical staining in CTX specimens, mainly in the neuron like cells and a small number of astrocyte like cells. In FCD Ia tissue, IL-1 beta /IL-1R1 presented a medium to strong expression. In the microcolumnar hypertrophic neurons of gray matter and gray matter and white matter junction, it is also expressed in some astrocytes like cells in the gray and white matter junction area; and in FCD IIa and FCD IIb specimens, IL-1 beta is strongly expressed in 89% + 6.2% DN (n=650) and 84% + 5.7% BC (n= 255). The immunofluorescence double standard results show IL-1 beta in FCD specimens. IL-1R1 showed strong immune activity, expressed in heteromorphic neurons DN and BC, CO labeled with neuron marker Neu N, and co labeled with most (80%) activated astrocytes (GFAP) and microglia (HLA). This expression was similar to P2X7R. Three, P2X7 receptor was in alkylate methyl azo methanol (methylazoxymethanol acetate, MAM). The expression and protein distribution in the model 1.MCD model rat cortical dysplasia model basic characteristics we use the alkyl methyl azo methanol (methylazoxymethanol acetate, MAM) to give pregnant rats intraperitoneal injection to induce the offspring to appear similar to the clinicopathological changes of cortical development obstacle, thus the animal simulation of MCD. The results suggest that MAM is large. The animal model of rat cortical development disorder showed small head deformity, decreased autonomic activity, slow response to external stimulation, decreased flexibility of crawling and avoidance action, decreased feeding ability, and weight loss. The main pathological manifestations were the thinning of the cortex, the indistinct structure of the lamina, the disorder of the cells, the abnormal neuronal morphology, and the enlargement of the cell body. The normal polarity disappeared, and a large number of heterotopic neurons were found on the molecular layer. The pathological nodules were clustered, and pathological nodules were seen with FCDII type pathological changes. The expression of the 2.P2X7 receptor m RNA in the MCD model cortex of CTX and MAM rats was used in Real-time PCR, immunohistochemical method, and the model of cortical dysplasia and normal control in MAM rats. The results showed that the expression of P2X7 m RNA in the cortex of MAM cortical dysplasia rats was significantly higher than that in the normal control group (CTX) in the same age group (CTX) in the different age group (2,4,6 weeks) of the MAM cortical dysplasia model, and the immunohistochemical method was used to compare the P2X7R, Caspase-1, IL-1 beta in the brain tissue of the MAM model rats. The results showed that P2X7R was weak to medium intensity expression in CTX normal control specimens of rats, but only in a small number of neuron like cells (22.9% + 3.4%, n=379), the weak expression was found on the glial cell like cells, while in the MAM cortical dysplasia tissue, the peri layer cells were arranged in disorder, and the expression of P2X7R was strongly expressed and widely distributed in the MAM cortical dysplasia. In gray matter and ash and white matter junction, the disorder, morphologically abnormal "heteromorphic neurons" and astrocytes, the same IL-1 beta, Caspase-1 in the cortex of MAM cortical dysplasia rats, m RNA and protein expression are significantly higher than those of CTX normal controls; the expression intensity of IL-1 beta and immunoreactive cells in the rat model of MAM cortical dysplasia model The number of P2X7R in CTX and FCD was analyzed for the first time from m RNA and protein levels. The results showed that the m RNA and protein expression of P2X7R in FCD patients was significantly higher than that of normal control CTX. The microcolumnar hypertrophic neurons in gray matter and white matter junction are also expressed in some glial cell like cells in the gray and white matter junction; in FCD IIa and FCD IIb specimens, P2X7R is strongly expressed in DN and BC, CO marked with the neuronal marker Neu N, and with most (80%) activated astrocytes (GFAP) and microglia. The expression of P2X7R m RNA and protein in the epileptic foci of.2.TSC patients was significantly higher than that of the control group. Compared with the CTX specimens, P2X7R was strongly expressed in more than 90% of DN in TSC specimens, and the.3. was in the epileptic focus of the patients with neuronal markers NF200 and astrocyte markers GFAP. The expression of A and protein were significantly higher than that of the normal control group.4.. Finally, we used the method of intraperitoneal injection of MAM to induce the MCD animal model in the pregnant rats. The effect of P2X7R on epileptic seizures was preliminarily verified. The results showed that the P2X7R agonist Bz ATP could lead to the seizure time obviously ahead of time and the seizures induced by bluka. We conclude that P2X7R and its Caspase1-I/L1 beta signaling pathway play an important role in epileptic seizure in MCD.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R742.1

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