本文選題：杜鵑素 + 小膠質(zhì)細(xì)胞��； 參考：《吉林大學(xué)》2017年碩士論文

【摘要】：近年來(lái),大量研究表明神經(jīng)炎癥在神經(jīng)退行性疾病的發(fā)生發(fā)展過(guò)程中起到重要作用。對(duì)死后PD病人剖檢及6-羥多巴胺(6-OHDA)和MPTP誘導(dǎo)的PD動(dòng)物模型中都發(fā)現(xiàn)中腦黑質(zhì)區(qū)存在小膠質(zhì)細(xì)胞異�；罨默F(xiàn)象。小膠質(zhì)細(xì)胞是神經(jīng)炎癥反應(yīng)的主要效應(yīng)細(xì)胞,其數(shù)量?jī)H占膠質(zhì)細(xì)胞總數(shù)的20%[1]。神經(jīng)炎癥過(guò)程中小膠質(zhì)細(xì)胞被過(guò)度活化后,能產(chǎn)生一些細(xì)胞毒性因子(IL-1β、IL-6、TNF-α、NO和PGE2等),這些細(xì)胞毒性因子可以導(dǎo)致周圍的神經(jīng)元發(fā)生損傷,損傷神經(jīng)元釋放的損傷相關(guān)模式分子可以進(jìn)一步活化小膠質(zhì)細(xì)胞,從而產(chǎn)生更多細(xì)胞毒性因子進(jìn)一步損傷周圍的神經(jīng)元[2]。目前已經(jīng)有研究表明,抗炎藥物能減少PD的患病率。因此,抑制小膠質(zhì)細(xì)胞活化可能對(duì)PD起到治療或緩解作用。杜鵑素(Farrerol)是提取自滿山紅或者其他杜鵑屬植物的一種黃酮類化合物,在體內(nèi)起到抗炎、抗氧化和免疫抑制等多方面的功能[3]。有研究結(jié)果顯示[4,5],杜鵑素在疾病中的很多積極作用都與其參與調(diào)節(jié)NF-κB通路的激活相關(guān);另外,杜鵑素可通過(guò)抑制促炎蛋白酶類(iNOS和COX-2)及其產(chǎn)物NO和PGE2來(lái)達(dá)到減輕炎癥的作用,所以,我們推測(cè)在PD中杜鵑素可能通過(guò)抑制神經(jīng)炎癥反應(yīng)從而對(duì)PD起到治療和緩解作用。因此,本實(shí)驗(yàn)通過(guò)建立LPS誘導(dǎo)的體外神經(jīng)炎癥反應(yīng)細(xì)胞模型和體內(nèi)PD動(dòng)物模型,研究了杜鵑素對(duì)神經(jīng)炎癥介導(dǎo)的PD模型的影響及其作用機(jī)制。通過(guò)對(duì)小膠質(zhì)細(xì)胞系BV-2細(xì)胞的研究發(fā)現(xiàn),杜鵑素對(duì)LPS誘導(dǎo)的炎癥模型中促炎細(xì)胞因子(IL-6、IL-1β和TNF-α)及促炎蛋白酶類(iNOS和COX-2)表達(dá)具有顯著的抑制作用,且呈劑量依賴性。同時(shí),杜鵑素也可以顯著抑制LPS誘導(dǎo)的BV-2細(xì)胞中NO和PGE2產(chǎn)量的增加。另外,通過(guò)Western blot方法檢測(cè)杜鵑素對(duì)LPS誘導(dǎo)的MAPKs、NF-κB和Akt信號(hào)通路關(guān)鍵節(jié)點(diǎn)磷酸化水平的影響,結(jié)果發(fā)現(xiàn)杜鵑素可以顯著抑制LPS誘導(dǎo)的NF-κB p65和Akt的磷酸化水平,但對(duì)MAPKs通路中ERK1/2、p38和JNK1/2的磷酸化水平?jīng)]有影響。以上結(jié)果表明,杜鵑素可以顯著抑制LPS在BV-2細(xì)胞中誘導(dǎo)的炎癥反應(yīng),其機(jī)制可能是通過(guò)抑制NF-κB p65和Akt的磷酸化。為了進(jìn)一步確定杜鵑素的抗神經(jīng)炎癥功能對(duì)PD的影響,我們通過(guò)在中腦黑質(zhì)區(qū)注射LPS建立PD動(dòng)物模型,并腹腔注射杜鵑素研究其對(duì)PD的治療作用。結(jié)果顯示,杜鵑素可以顯著抑制阿撲嗎啡誘導(dǎo)的PD動(dòng)物模型的旋轉(zhuǎn)行為;機(jī)制研究發(fā)現(xiàn),杜鵑素顯著抑制PD動(dòng)物模型中中腦黑質(zhì)區(qū)小膠質(zhì)細(xì)胞的激活以及多巴胺能神經(jīng)元的減少。以上研究結(jié)果表明,杜鵑素可以通過(guò)抑制NF-κB-p65和Akt的磷酸化改善LPS在小膠質(zhì)細(xì)胞中誘導(dǎo)的炎癥反應(yīng);此外,杜鵑素在PD動(dòng)物模型中通過(guò)抑制小膠質(zhì)細(xì)胞介導(dǎo)的神經(jīng)炎癥反應(yīng)過(guò)程中對(duì)多巴胺能神經(jīng)元起到保護(hù)作用。因此,杜鵑素有望成為PD治療的有效藥物。
[Abstract]:In recent years, a large number of studies have shown that neuroinflammation plays an important role in the occurrence and development of neurodegenerative diseases. Abnormal activation of microglia in substantia nigra was found in postmortem PD patients, 6-OHDA (6-OHDA) and MPTP induced PD animal models. Microglial cells are the main effector cells of neuroinflammatory reaction, which only account for 20% of the total number of glial cells [1]. In the process of neuroinflammation, microglia are over-activated and produce some cytotoxic factors (IL-1 尾, IL-6, TNF- 偽, no, PGE2, etc.). These cytokines can cause damage to the surrounding neurons. Injury-related model molecules released by injured neurons can further activate microglia and produce more cytotoxic factors to further damage the surrounding neurons [2]. Studies have shown that anti-inflammatory drugs can reduce the prevalence of PD. Therefore, inhibition of microglial activation may play a therapeutic or remission role in PD. Farrerol is a flavonoid extracted from Rhododendron or other Rhododendron plants. Farrerol has many functions of anti-inflammatory, anti-oxidation and immunosuppressive in vivo [3]. Some studies have shown that Rhododendron is involved in regulating the activation of NF- 魏 B pathway in many of its positive roles in the disease. In addition, rhododendronin can attenuate inflammation by inhibiting proinflammatory proteases (iNOS and COX-2) and their products, no and PGE2. Therefore, we speculate that rhododendron may play a therapeutic and remission role in PD by inhibiting neuroinflammatory response. Therefore, the effects of rhododendron on neuroinflammatory PD model induced by LPS in vitro and PD animal model in vivo were studied. Through the study of microglial cell line BV-2, it was found that rhododendron inhibited the expression of pro-inflammatory cytokines (IL-6, IL-1 尾 and TNF- 偽) and pro-inflammatory proteases (iNOS and COX-2) in a dose-dependent manner. At the same time, rhododendron could significantly inhibit the increase of no and PGE2 production in BV-2 cells induced by LPS. In addition, the effects of rhododendron on LPS-induced phosphorylation of NF- 魏 B and Akt key nodes in MAPK- 魏 B and Akt signaling pathway were detected by Western blot. The results showed that Rhododendron could significantly inhibit the phosphorylation of LPS-induced NF- 魏 B p65 and Akt. But there was no effect on the phosphorylation levels of ERK1 / 2 p38 and JNK1 / 2 in MAPKs pathway. These results suggest that Rhododendron can significantly inhibit the inflammatory response induced by LPS in BV-2 cells by inhibiting the phosphorylation of NF- 魏 B p65 and Akt. In order to further determine the effect of rhododendron on PD, we established PD animal model by injecting LPS into substantia nigra of mesencephalon, and intraperitoneally injected rhododendron to study the therapeutic effect of Rhododendron on PD. The results showed that rhododendron could significantly inhibit the rotational behavior of PD model induced by apomorphine. Rhododendron significantly inhibited the activation of microglia and the decrease of dopaminergic neurons in substantia nigra in PD animal model. These results suggest that Rhododendron can improve the LPS-induced inflammatory response in microglia by inhibiting the phosphorylation of NF- 魏 B-p65 and Akt. Rhododendron protects dopaminergic neurons by inhibiting neuroinflammatory responses mediated by microglia in PD animal models. Therefore, rhododendron is expected to be an effective drug in the treatment of PD.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R285.5;R-332

【參考文獻(xiàn)】

相關(guān)博士學(xué)位論文 前2條

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2 慈鑫鑫;杜鵑素對(duì)卵蛋白和內(nèi)毒素誘導(dǎo)氣道炎癥的作用及機(jī)制研究[D];吉林大學(xué);2012年

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本文編號(hào)：2118198