本文選題：帕金森病　切入點(diǎn)：6-羥多巴胺　出處：《福建醫(yī)科大學(xué)》2014年碩士論文　論文類型：學(xué)位論文

【摘要】：帕金森病(Parkinson,s disease，PD)是一種常見的神經(jīng)系統(tǒng)退行性疾病，以中腦黑質(zhì)致密部多巴胺（DA）能神經(jīng)元變性壞死和出現(xiàn)Lewy小體為主要病理特點(diǎn)。左旋多巴（L-Dopa）是PD治療上的主要藥物之一，目前關(guān)于L-Dopa的毒性存在爭議，長期的動物體內(nèi)研究與臨床研究結(jié)論不一。6-OHDA制作的PD模型能模擬PD的病理過程，模型中可以觀察到小膠質(zhì)細(xì)胞的激活及炎癥因子TNF-α等增加，最終介導(dǎo)DA能神經(jīng)元的缺失。本實驗以6-OHDA的PD模型為對照，觀察L-Dopa的腦內(nèi)直接注射以及灌胃給藥能否產(chǎn)生類似6-OHDA的毒性，引起小膠質(zhì)細(xì)胞的增生激活并介導(dǎo)DA能神經(jīng)元的損傷，初步探討L-Dopa可能的毒性，為臨床L-Dopa的安全合理用藥提供依據(jù)。 1、方法： （1）取SD大鼠，隨機(jī)分成實驗組與對照組，實驗組大鼠左側(cè)紋狀體內(nèi)分別注射6-OHDA(5ug/uL)、不同劑量L-Dopa（50ug/uL、5ug/uL、1ug/uL），對照組注射等量生理鹽水； （2）取SD大鼠，隨機(jī)分成實驗組與對照組，實驗組大鼠灌胃分別給不同劑量L-Dopa（200mg/kg.d、100mg/kg.d、10mg/kg.d），對照組注射等量生理鹽水； （3）術(shù)后觀察各組經(jīng)阿樸嗎啡誘導(dǎo)后大鼠旋轉(zhuǎn)行為的改變； （4）術(shù)后4周取實驗組和對照組腦組織行免疫組織化學(xué)染色，觀察黑質(zhì)DA能神經(jīng)元數(shù)量變化；行免疫熒光技術(shù)染色,觀察大鼠中腦黑質(zhì)致密部中的小膠質(zhì)細(xì)胞激活情況及TNF-α水平的改變； 2、結(jié)果： （1）與對照組相比，術(shù)后4周6-OHDA誘導(dǎo)的PD大鼠模型可觀察到腦黑質(zhì)中小膠質(zhì)細(xì)胞的激活（P0.001）、TNF-α水平的增高（P0.001）及DA能神經(jīng)元的減少（P0.001）； （2）與對照組相比，術(shù)后4周直接腦內(nèi)注射高劑量L-Dopa的正常大鼠可觀察到腦黑質(zhì)中小膠質(zhì)細(xì)胞的激活（P0.05）、TNF-α水平的增高（P0.05）及DA能神經(jīng)元的減少（P0.05）； （3）與對照組相比，術(shù)后4周正常大鼠直接腦內(nèi)注射中、低劑量L-Dopa、灌胃給各劑量L-Dopa未發(fā)現(xiàn)腦黑質(zhì)中小膠質(zhì)細(xì)胞的激活（P0.05）、TNF-α水平的增高（P0.05）及DA能神經(jīng)元的減少（P0.05）。 3、結(jié)論： （1）健康大鼠腦內(nèi)直接注射高濃度L-Dopa可產(chǎn)生與6-OHDA相似的神經(jīng)毒性，即引起小膠質(zhì)細(xì)胞的激活及DA能神經(jīng)元的受損，但一般口服劑量L-Dopa對健康大鼠沒有發(fā)現(xiàn)神經(jīng)毒性。 （2）不能排除在腦內(nèi)已有嚴(yán)重病理變化的情況下，口服大劑量L-Dopa對DA能神經(jīng)元產(chǎn)生毒性的可能性。
[Abstract]:Parkinsonian disease (PDD) is a common neurodegenerative disease, characterized by degeneration and necrosis of dopaminergic neurons in the substantia nigra compact region and the presence of Lewy corpuscles. L-Dopaus is one of the main drugs in the treatment of PD. At present, the toxicity of L-Dopa is controversial. The PD model made by 6-OHDA can simulate the pathological process of PD. The activation of microglia and the increase of inflammatory factor TNF- 偽 can be observed in the model. In this experiment, we used the PD model of 6-OHDA as the control, to observe whether L-Dopa could produce the toxicity similar to 6-OHDA, induce the proliferation and activation of microglia and mediate the damage of DA neurons. To explore the possible toxicity of L-Dopa and to provide evidence for the safe and rational use of L-Dopa. 1. Methods:. Sprague-Dawley rats were randomly divided into experimental group and control group. The left striatum of experimental group was injected with 6-OHDA-5ug-uLX respectively. The rats in the control group were injected with the same amount of normal saline. (2) Sprague-Dawley rats were randomly divided into experimental group and control group. Rats in the experimental group were given different doses of L-Dopaus 200mg / kg / kg / kg / 100 mg / kg / kg / kg / kg / d respectively, and the control group was injected with the same amount of normal saline. The rotation behavior of rats induced by apomorphine was observed after operation. Four weeks after operation, the brain tissues of the experimental group and the control group were taken for immunohistochemical staining to observe the changes of DA neurons in the substantia nigra, and immunofluorescence staining was performed to observe the changes of DA neurons in the substantia nigra. The activation of microglia and the level of TNF- 偽 in the substantia nigra were observed. 2. Results:. (1) compared with the control group, the PD rat model induced by 6-OHDA at 4 weeks after operation showed the increase of the level of TNF- 偽 and the decrease of dopaminergic neurons in the substantia nigra (P 0.001) and the decrease of dopaminergic neurons (P 0.001). (2) compared with the control group, 4 weeks after operation, the normal rats injected with high dose L-Dopa directly into the brain could observe the increase of the level of TNF- 偽 in the substantia nigra and the decrease of dopaminergic neurons (P0.05). (3) compared with the control group, low dose L-Dopaas and intragastric administration of L-Dopa did not show the increase in the level of TNF- 偽 and the decrease of dopaminergic neurons in the substantia nigra (P0.05) and the decrease of DA neurons in normal rats 4 weeks after operation. 3. Conclusion:. 1) the neurotoxicity of L-Dopa was similar to that of 6-OHDA, that is, the activation of microglia and the damage of DA neurons were induced by direct intracerebral injection of L-Dopa into the brain of healthy rats, but no neurotoxicity was found in healthy rats at the general oral dose of L-Dopa. 2) the possibility of toxicity of high dose L-Dopa to DA neurons can not be ruled out in the presence of severe pathological changes in the brain.
【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R742.5

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