堿性成纖維細(xì)胞生長因子對帕金森病神經(jīng)遞質(zhì)的影響及其保護(hù)機(jī)制研究
發(fā)布時間：2018-11-28 09:22
【摘要】：帕金森病(Parkinson's disease, PD)是一種好發(fā)于中老年人的中樞神經(jīng)退行性疾病,主要病理特征在于黑質(zhì)-紋狀體內(nèi)多巴胺(DA)能神經(jīng)元的變性,導(dǎo)致腦部神經(jīng)遞質(zhì)DA缺乏。PD病變復(fù)雜,發(fā)病機(jī)制尚未完全闡明,普遍認(rèn)為是一種與一些神經(jīng)遞質(zhì)系統(tǒng)相關(guān)的可逐漸惡化的多中心神經(jīng)變性疾病,其臨床癥狀主要表現(xiàn)為靜止性震顫、運(yùn)動遲緩、肌僵直和姿勢平衡障礙。帕金森病手術(shù)治療昂貴,目前還是以藥物治療為主。但已有的抗帕金森病藥物只起著改善癥狀的作用,不能延緩疾病的進(jìn)程,不能預(yù)防DA能神經(jīng)元的退變,且長期服用,其用量越來越大,副作用越來越多。近年來,帕金森病藥物治療由直接補(bǔ)充DA轉(zhuǎn)向多環(huán)節(jié)治療,重點(diǎn)集中于對DA能神經(jīng)元的保護(hù)作用。目前許多研究者關(guān)注應(yīng)用神經(jīng)營養(yǎng)因子和生長因子治療帕金森病,其中堿性成纖維細(xì)胞生長因子(bFGF)作為一類生長因子,具有促有絲分裂的作用,在人體組織上含有豐富的受體,在體內(nèi)和體外均具有活性,主要通過與細(xì)胞表面的酪氨酸激酶型受體作用而發(fā)揮著廣泛的生物學(xué)功能,在組織創(chuàng)傷修復(fù)和神經(jīng)保護(hù)等方面起著重要的作用。 本論文從PD病變源頭—神經(jīng)元的營養(yǎng)修護(hù)角度,從動物行為學(xué)、神經(jīng)遞質(zhì)含量、神經(jīng)元數(shù)目等方面的變化來研究bFGF對PD腦內(nèi)神經(jīng)遞質(zhì)的影響,并通過檢測多種相關(guān)生化指標(biāo)初步來闡明bFGF修護(hù)神經(jīng)元和影響PD神經(jīng)遞質(zhì)可能的作用機(jī)制。具體內(nèi)容包括以下三點(diǎn)： (1)建立了由神經(jīng)毒素6-羥基多巴(6-OHDA)誘發(fā)的帕金森病細(xì)胞模型。在細(xì)胞水平上,bFGF能夠提高帕金森病PC12模型細(xì)胞的成活率,降低6-OHDA引起的PC12細(xì)胞凋亡,促進(jìn)細(xì)胞中相關(guān)單胺類神經(jīng)遞質(zhì)及其代謝產(chǎn)物的分泌,刺激帕金森病模型細(xì)胞中酪氨酸羥化酶(TH)的表達(dá)。同時bFGF能提高帕金森病模型細(xì)胞中磷酸化Akt和ERK的蛋白水平,抑制細(xì)胞中內(nèi)質(zhì)網(wǎng)應(yīng)激蛋白(CHOP、GRP78和CASPASE12)的表達(dá),提示bFGF可能通過激活PI3K/Akt和ERK1/2通路來抑制6-OHDA氧化損傷引起的內(nèi)質(zhì)網(wǎng)應(yīng)激,降低神經(jīng)細(xì)胞凋亡,從而實(shí)現(xiàn)神經(jīng)保護(hù)作用。 (2)采用腦立體定位注射6-OHDA構(gòu)建了PD大鼠偏側(cè)模型,并通過腹腔注射阿撲嗎啡溶液引起的動物行為學(xué)來驗(yàn)證模型的成功。在動物水平上,bFGF可以有效改善模型動物的帕金森病癥狀；提高大鼠腦紋狀體組織中細(xì)胞外液和細(xì)胞內(nèi)外總的單胺類神經(jīng)遞質(zhì)含量；促進(jìn)腦部黑質(zhì)和紋狀體中TH的表達(dá)。此外,bFGF能促進(jìn)PD大鼠腦內(nèi)自由基的清除,上調(diào)PD大鼠損毀側(cè)紋狀體中磷酸化Akt和ERK的水平,抑制內(nèi)質(zhì)網(wǎng)應(yīng)激蛋白(CHOP、GRP78和CASPASE12)以及α-Syn蛋白的表達(dá),提示bFGF可能通過激活PI3K/Akt和ERK1/2通路,抑制6-OHDA氧化損傷引起的內(nèi)質(zhì)網(wǎng)應(yīng)激和α-Syn蛋白水平,促使TH的表達(dá)提高,降低DA能神經(jīng)元凋亡,增加神經(jīng)遞質(zhì)的合成,最終表現(xiàn)出PD癥狀改善,實(shí)現(xiàn)帕金森病的神經(jīng)保護(hù)作用。 (3)以基于1HNMR的代謝組學(xué)方法對PD大鼠腦紋狀體進(jìn)行研究,發(fā)現(xiàn)PD大鼠腦紋狀體中乳酸、γ-氨基丁酸、谷氨酸、肌酸、甘氨酸和肌醇含量增加；N-乙酰天門冬氨酸、�；撬岬暮繙p少。提示PD腦中形成了興奮性毒性,參與了DA能神經(jīng)元凋亡。經(jīng)過bFGF治療后,PD大鼠腦紋狀體中γ-氨基丁酸、N-乙酰天門冬氨酸和�；撬岬暮棵黠@上升；谷氨酸、肌醇和乳酸的含量明顯下降。表明bFGF能使紋狀體中失衡的氨基酸類神經(jīng)遞質(zhì)向常態(tài)恢復(fù),改善星形膠質(zhì)細(xì)胞增生,促進(jìn)星形膠質(zhì)細(xì)胞營養(yǎng)因子的分泌,對DA能神經(jīng)元具有營養(yǎng)和修護(hù)作用。 總而言之,本論文研究了bFGF用藥前后帕金森病神經(jīng)遞質(zhì)的變化,以及內(nèi)質(zhì)網(wǎng)應(yīng)激和a-Syn蛋白表達(dá)等生化指標(biāo)變化來探討bFGF對帕金森病的保護(hù)作用,為bFGF能改善PD癥狀提供了一個新的可闡明的機(jī)制,其研究結(jié)果可為設(shè)計(jì)新型的PD治療藥物和建立PD治療策略提供實(shí)驗(yàn)依據(jù)。此外,首次采用代謝組學(xué)方法,從系統(tǒng)生物學(xué)層面上發(fā)現(xiàn)了PD腦中一些代謝異常的氨基酸類小分子,為帕金森病的發(fā)病機(jī)制、發(fā)展演化以及治療研究提供新的研究思路。
[Abstract]:Parkinson's disease (PD) is a kind of central nervous system of the middle-aged and the elderly. The main pathological features are the degeneration of the dopaminergic neurons in the substantia nigra-striatal, which leads to the lack of the DA in the brain. PD is a complex disease, and the pathogenesis has not yet been fully set forth. It is generally believed to be a progressive, multi-center neurodegenerative disease associated with some neurotransmitter systems. The clinical symptoms of PD are mainly static tremor, bradykinesia, muscle stiffness and postural balance disorder. The treatment of Parkinson's disease is expensive, and is currently based on drug therapy. However, the anti-Parkinson's disease has the effect of improving the symptoms only, can not delay the process of the disease, can not prevent the detransformation of the DA energy neuron, and is taken for a long time, the dosage of the anti-Parkinson's disease drug is more and more large, and the side effect is more and more. In recent years, the treatment of Parkinson's disease is controlled by the direct supplement of DA to multi-link therapy, focusing on the protection of DA energy neurons. At present, many researchers are concerned about the application of neurotrophin and growth factors to the treatment of parkinson's disease, in which basic fibroblast growth factor (bFGF), as a kind of growth factor, has a mitogenic effect, In vivo and in vitro, the activity mainly plays an important role in tissue wound repair and neuroprotection by playing a wide range of biological functions through the role of the tyrosine kinase-like receptors on the surface of the cells. In this paper, the effects of bFGF on neurotransmitters in PD were studied from the aspects of animal behavior, neurotransmitter content and number of neurons from the perspective of the nutritional repair of the source of PD. In response, and through the detection of a variety of related biochemical indexes, the effect of the bFGF on the repair of the neurons and the potential of the PD neurotransmitters is explained. The specific contents of the system are as follows: Point: (1) The establishment of a fine Parkinson's disease induced by neurotoxin 6-hydroxydopamine (6-OHDA) In cell level, bFGF can improve the survival rate of PC12 model cells, decrease the apoptosis of PC12 cells induced by 6-OHDA, promote the secretion of the related monoamines and their metabolites in the cells, and stimulate the tyrosine hydroxylase (TH) in the model cells of Parkinson's disease. The expression of bFGF can improve the protein level of phosphorylated Akt and ERK in the model cells of Parkinson's disease, and inhibit the expression of endoplasmic reticulum stress protein (CHOP, GRP78 and CASPASE12) in the cells. It is suggested that bFGF may inhibit the endoplasmic reticulum stress caused by the oxidative damage of 6-OHDA by activating the PI3K/ Akt and ERK1/ 2 pathways, and reduce the nerve fine. Apoptosis, thus realizing neuroprotection (2) The partial side model of PD rats was constructed by stereotaxic injection of 6-OHDA and the behavior of animal behavior caused by injection of apomorphine in the abdominal cavity was verified. The success of the model is that, at the animal level, bFGF can effectively improve the symptoms of the Parkinson's disease in the model animals, improve the content of the monoamines in the extracellular fluid and the inside and outside the cells of the rat brain striatal tissue, and promote the substantia nigra and the striatum of the brain. In addition, bFGF can promote the clearance of free radicals in the brain of PD rats, increase the level of phosphorylated Akt and ERK in the rat striatum of PD rats, and inhibit the expression of endoplasmic reticulum stress protein (CHOP, GRP78 and CASPASE12), and the expression of HCO3-Syn protein, suggesting that bFGF may activate PI3K/ Akt and ERK by activating PI3K/ Akt and ERK. 1/ 2 pathway, to inhibit the endoplasmic reticulum stress and the P-Syn protein level caused by the 6-OHDA oxidative damage, to promote the expression of TH, to reduce the apoptosis of the DA and to increase the synthesis of the neurotransmitters, and finally to show the improvement of the PD symptoms and the realization of the God of the Parkinson's disease. (3) The brain striatum of PD rats was studied by means of a metabolic group based on 1HNMR, and the content of lactic acid, L-aminobutyric acid, glutamic acid, myoacid, glycine and inositol increased in the striatum of PD rats. The content of the sulfonic acid is reduced. It is suggested that the PD brain forms an excitable toxicity and is involved in D A. The content of P-aminobutyric acid, N-glycinate and taurine in the striatum of PD rats increased significantly after the treatment of bFGF. Glutamic acid, inositol and lactic acid The results showed that bFGF can restore the unbalanced amino acid neurotransmitters in the striatum to normal state, improve the proliferation of astrocytes, promote the secretion of the nutrient factors of astrocytes, and have the effects on the dopaminergic neurons. The effects of bFGF on the protective effect of bFGF on parkinson's disease were discussed in this paper. A new eluctable mechanism, the results of which can be designed to design new PD-treated drugs and to establish PD The experimental basis for the therapeutic strategy is provided. In addition, the metabolic group learning method is adopted for the first time, and the amino acid type small molecules of some metabolic abnormalities in the PD brain are found at the systemic biological level, and the pathogenesis, the development and the evolution of the Parkinson's disease and the treatment of the disease are developed.
【學(xué)位授予單位】：南京理工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R742.5
本文編號：2362449
[Abstract]:Parkinson's disease (PD) is a kind of central nervous system of the middle-aged and the elderly. The main pathological features are the degeneration of the dopaminergic neurons in the substantia nigra-striatal, which leads to the lack of the DA in the brain. PD is a complex disease, and the pathogenesis has not yet been fully set forth. It is generally believed to be a progressive, multi-center neurodegenerative disease associated with some neurotransmitter systems. The clinical symptoms of PD are mainly static tremor, bradykinesia, muscle stiffness and postural balance disorder. The treatment of Parkinson's disease is expensive, and is currently based on drug therapy. However, the anti-Parkinson's disease has the effect of improving the symptoms only, can not delay the process of the disease, can not prevent the detransformation of the DA energy neuron, and is taken for a long time, the dosage of the anti-Parkinson's disease drug is more and more large, and the side effect is more and more. In recent years, the treatment of Parkinson's disease is controlled by the direct supplement of DA to multi-link therapy, focusing on the protection of DA energy neurons. At present, many researchers are concerned about the application of neurotrophin and growth factors to the treatment of parkinson's disease, in which basic fibroblast growth factor (bFGF), as a kind of growth factor, has a mitogenic effect, In vivo and in vitro, the activity mainly plays an important role in tissue wound repair and neuroprotection by playing a wide range of biological functions through the role of the tyrosine kinase-like receptors on the surface of the cells. In this paper, the effects of bFGF on neurotransmitters in PD were studied from the aspects of animal behavior, neurotransmitter content and number of neurons from the perspective of the nutritional repair of the source of PD. In response, and through the detection of a variety of related biochemical indexes, the effect of the bFGF on the repair of the neurons and the potential of the PD neurotransmitters is explained. The specific contents of the system are as follows: Point: (1) The establishment of a fine Parkinson's disease induced by neurotoxin 6-hydroxydopamine (6-OHDA) In cell level, bFGF can improve the survival rate of PC12 model cells, decrease the apoptosis of PC12 cells induced by 6-OHDA, promote the secretion of the related monoamines and their metabolites in the cells, and stimulate the tyrosine hydroxylase (TH) in the model cells of Parkinson's disease. The expression of bFGF can improve the protein level of phosphorylated Akt and ERK in the model cells of Parkinson's disease, and inhibit the expression of endoplasmic reticulum stress protein (CHOP, GRP78 and CASPASE12) in the cells. It is suggested that bFGF may inhibit the endoplasmic reticulum stress caused by the oxidative damage of 6-OHDA by activating the PI3K/ Akt and ERK1/ 2 pathways, and reduce the nerve fine. Apoptosis, thus realizing neuroprotection (2) The partial side model of PD rats was constructed by stereotaxic injection of 6-OHDA and the behavior of animal behavior caused by injection of apomorphine in the abdominal cavity was verified. The success of the model is that, at the animal level, bFGF can effectively improve the symptoms of the Parkinson's disease in the model animals, improve the content of the monoamines in the extracellular fluid and the inside and outside the cells of the rat brain striatal tissue, and promote the substantia nigra and the striatum of the brain. In addition, bFGF can promote the clearance of free radicals in the brain of PD rats, increase the level of phosphorylated Akt and ERK in the rat striatum of PD rats, and inhibit the expression of endoplasmic reticulum stress protein (CHOP, GRP78 and CASPASE12), and the expression of HCO3-Syn protein, suggesting that bFGF may activate PI3K/ Akt and ERK by activating PI3K/ Akt and ERK. 1/ 2 pathway, to inhibit the endoplasmic reticulum stress and the P-Syn protein level caused by the 6-OHDA oxidative damage, to promote the expression of TH, to reduce the apoptosis of the DA and to increase the synthesis of the neurotransmitters, and finally to show the improvement of the PD symptoms and the realization of the God of the Parkinson's disease. (3) The brain striatum of PD rats was studied by means of a metabolic group based on 1HNMR, and the content of lactic acid, L-aminobutyric acid, glutamic acid, myoacid, glycine and inositol increased in the striatum of PD rats. The content of the sulfonic acid is reduced. It is suggested that the PD brain forms an excitable toxicity and is involved in D A. The content of P-aminobutyric acid, N-glycinate and taurine in the striatum of PD rats increased significantly after the treatment of bFGF. Glutamic acid, inositol and lactic acid The results showed that bFGF can restore the unbalanced amino acid neurotransmitters in the striatum to normal state, improve the proliferation of astrocytes, promote the secretion of the nutrient factors of astrocytes, and have the effects on the dopaminergic neurons. The effects of bFGF on the protective effect of bFGF on parkinson's disease were discussed in this paper. A new eluctable mechanism, the results of which can be designed to design new PD-treated drugs and to establish PD The experimental basis for the therapeutic strategy is provided. In addition, the metabolic group learning method is adopted for the first time, and the amino acid type small molecules of some metabolic abnormalities in the PD brain are found at the systemic biological level, and the pathogenesis, the development and the evolution of the Parkinson's disease and the treatment of the disease are developed.
【學(xué)位授予單位】：南京理工大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R742.5
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