香兰素在神经炎症介导的帕金森病模型中的作用

发布时间：2018-05-13 12:32

本文选题：帕金森病 + 神经炎症　；参考：《吉林大学》2017年硕士论文

【摘要】：帕金森病(PD)是一种常见的神经退行性疾病,多发于中老年时期,近年来有年轻化的趋势。PD的病因尚不明确,目前大量研究表明小胶质细胞介导的神经炎症反应在其发生发展过程中起到至关重要的作用。小胶质细胞是神经胶质细胞的一种,其是神经炎症反应的主要效应细胞,与外周系统中的巨噬细胞功能相似。小胶质细胞过度活化后能产生TNF-α、IL-1β和IL-6等炎性介质,后者可以对多巴胺能神经元产生损伤,多巴胺能神经元的损伤信号又可以进一步加剧小胶质细胞活化,从而形成恶性循环。因此,抑制小胶质细胞介导的神经炎症反应可能是PD的一个潜在治疗措施。香兰素是一种芳香醛类化合物,其为天然香草的主要成分之一,目前被广泛用作香料和食品添加剂。香兰素在肝脏、结肠及巨噬细胞等外周组织和细胞中能起到广泛的抗炎作用。另外,香兰素在鱼藤酮诱导的动物模型中能起到缓解PD的作用,但是机制尚不明确。因此,我们推测香兰素可能通过抑制小胶质细胞介导的神经炎生反应,从而对PD起到治疗作用。基于此,本文第一部分实验应用脑立体定位技术向大鼠中脑黑质区注射脂多糖(LPS)建立神经炎症介导的PD大鼠模型,腹腔注射不同剂量的香兰素后检测其对模型鼠旋转行为、中脑黑质区多巴胺能神经元损伤及小胶质细胞活化的影响。结果表明,黑质区注射LPS后腹腔注射阿扑吗啡可诱导PD模型鼠出现旋转行为。腹腔注射不同剂量的香兰素(5mg/kg/day、10mg/kg/day和20mg/kg/day)后于建模第二周和第四周观测其旋转行为,结果发现香兰素能剂量和时间依赖性缓解阿扑吗啡诱导的旋转行为;黑质区注射LPS后黑质区多巴胺能神经元损伤和小胶质细胞活化程度增强,香兰素能浓度依赖性保护多巴胺能神经元并抑制小胶质细胞活化。这些结果表明香兰素可能在神经炎症介导的PD中通过抑制小胶质细胞活化,从而对多巴胺能神经元起到神经保护作用。基于第一部分发现,第二部分实验通过体外LPS诱导的小胶质细胞炎症反应模型,添加香兰素后检测其对胶质细胞炎症反应的影响及其机制。研究发现香兰素能够抑制相关炎性因子和促炎酶类m RNA和蛋白表达水平;香兰素抑制了MAPK p38,ERK1/2和NF-κB p65磷酸化,而对JNK的磷酸化没有明显作用。以上结果表明,香兰素可通过抑制小胶质细胞介导的神经炎症对PD大鼠模型起到治疗或缓解作用。因此,香兰素可能是治疗PD的潜在有效药物。
[Abstract]:Parkinson's disease (PD) is a common neurodegenerative disease, mostly in the middle and old age. The etiology of PD is not clear in recent years. A large number of studies have shown that neuroinflammation mediated by microglia plays an important role in the development of neuroinflammation. Microglia are one of the neuroglial cells, which are the main effector cells of neuroinflammatory response, and have similar functions to macrophages in peripheral system. Over activation of microglia can produce inflammatory mediators such as TNF- 伪 IL-1 尾 and IL-6, the latter can damage dopaminergic neurons, and the damage signals of dopaminergic neurons can further aggravate the activation of microglia and form a vicious circle. Therefore, inhibition of neuroinflammation mediated by microglia may be a potential therapy for PD. Vanillin is an aromatic aldehydes, which is one of the main components of natural herbs, and is widely used as spices and food additives. Vanillin has a wide range of anti-inflammatory effects in peripheral tissues and cells such as liver, colon and macrophage. In addition, vanillin can alleviate PD in rotenone-induced animal models, but the mechanism is unclear. Therefore, we speculate that vanillin may play a therapeutic role in PD by inhibiting microglia mediated neuritis. In the first part of this paper, the rat model of PD induced by neuroinflammation was established by injecting lipopolysaccharide (LPSs) into the substantia nigra of rat with stereotactic technique. The rotational behavior of PD rats was measured after different doses of vanillin was injected intraperitoneally. Injury of dopaminergic neurons in substantia nigra and effect of microglia activation. The results showed that injecting apomorphine intraperitoneally into the substantia nigra LPS could induce rotational behavior in PD mice. Different doses of vanillin were injected intraperitoneally with 5 mg / kg 路kg ~ (-1) 路kg ~ (-1) / day and 20 mg / kg / day respectively. The rotation behavior was observed in the second and fourth week of modeling. The results showed that vanillin could attenuate the rotational behavior induced by apomorphine in a dose-and time-dependent manner. The injury of dopaminergic neurons and the activation of microglia in substantia nigra were increased after LPS injection. Vanillin could protect dopaminergic neurons and inhibit the activation of microglia in a concentration-dependent manner. These results suggest that vanillin may play a neuroprotective role on dopaminergic neurons by inhibiting the activation of microglia in PD mediated by neuroinflammation. Based on the results of the first part, in the second part, the effects of vanillin on the inflammatory response of microglia induced by LPS in vitro and its mechanism were detected. It was found that vanillin could inhibit the expression of related inflammatory factors and proinflammatory enzymes m RNA and protein, and vanillin inhibited the phosphorylation of MAPK p38 ERK1 / 2 and NF- 魏 B p65, but had no effect on the phosphorylation of JNK. These results suggest that vanillin can inhibit neuroinflammation mediated by microglia in PD rats. Therefore, vanillin may be a potential effective drug in the treatment of PD.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R742.5;R-332

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