本文關(guān)鍵詞： FCPR03 PDE4抑制劑 抑郁癥 脂多糖 細胞因子 神經(jīng)炎癥　出處：《南方醫(yī)科大學》2017年碩士論文　論文類型：學位論文

【摘要】：目的:抑郁癥是由多種因素引起的,以持續(xù)心境低落為主要臨床特征的情感性精神障礙,是一個世界性的重大心理健康問題。近年來,隨著現(xiàn)代生活節(jié)律的不斷加快,社會壓力的逐漸增大,抑郁癥的發(fā)病率也呈逐年升高的趨勢。許多的研究認為抑郁癥的發(fā)病與中樞的炎癥過程有著密切聯(lián)系,同時越來越多的研究也表明炎癥在抑郁癥的發(fā)生和發(fā)展過程中具有重要作用,抑郁癥和中樞炎癥之間有著某種密切聯(lián)系。大量研究顯示PDE4抑制劑在體內(nèi)外均具有顯著的抗炎作用,同時還能夠通過上調(diào)cAMP/PKA/CREB信號通路產(chǎn)生抗抑郁的作用,然而因具有嚴重的惡心嘔吐不良反應(yīng),限制了其在臨床上的進一步應(yīng)用。FCPR03是本課題組自主設(shè)計并合成的新型PDE4抑制劑,前期的實驗結(jié)果顯示對PDE4具有很高的選擇性�；谝钟舭Y的神經(jīng)炎癥假說,本課題利用LPS建立炎癥誘導(dǎo)的小鼠抑郁癥模型,評價FCPR03對LPS誘導(dǎo)的小鼠抑郁樣行為的改善作用,同時利用LPS誘導(dǎo)BV-2小膠質(zhì)細胞的活化作為體外神經(jīng)炎癥模型,探討FCPR03的抗神經(jīng)炎癥作用及其機制研究,為尋找能夠改善由炎癥誘導(dǎo)抑郁癥的藥物提供理論基礎(chǔ)。方法:(1)采用抑郁癥行為絕望模型中懸尾和強迫游泳實驗初步探討FCPR03的抗抑郁作用。(2)建立LPS誘導(dǎo)小鼠抑郁樣行為動物模型,對小鼠腹腔注射1.2mg/kg LPS作為炎癥誘導(dǎo)的小鼠抑郁癥模型,評價FCPR03對LPS誘導(dǎo)小鼠抑郁樣行為的改善作用及其相關(guān)機制的研究。(3)利用1 μg/mlLPS誘導(dǎo)BV-2小膠質(zhì)細胞活化模擬體外神經(jīng)炎癥模型,評價FCPR03的體外抗神經(jīng)炎癥作用。(4)通過觀察氯胺酮/賽拉嗪聯(lián)合誘導(dǎo)小鼠翻正反射從消失到恢復(fù)所需時間以及比格犬的致嘔吐實驗來評價FCPR03的致嘔吐潛能。結(jié)果:(1)和正常組相比,小鼠腹腔注射不同劑量FCPR03 30 min后,在曠場實驗中的水平得分和垂直得分均沒有統(tǒng)計學差異;而在懸尾和強迫游泳實驗中,小鼠不動時間顯著降低,表明FCPR03具有潛在的抗抑郁作用。(2)對小鼠腹腔注射1.2mg/kgLPS24h后,小鼠體重顯著降低,同時在懸尾和強迫游泳實驗中小鼠不動時間顯著增加,糖水偏嗜度明顯降低,而連續(xù)7天灌胃給予FCPR03后,能夠降低小鼠在行為學中的不動時間,增加小鼠的糖水偏嗜度,提示FCPR03可以改善LPS誘導(dǎo)的小鼠抑郁樣行為。(3)進一步的研究發(fā)現(xiàn),FCPR03可能是通過上調(diào)cAMP/PKA/CREB信號通路,增加皮層和海馬內(nèi)BDNF的表達,降低p38和JNK的磷酸化水平,抑制NF-κB的活化,從而抑制炎癥因子的釋放,抑制中樞的神經(jīng)炎癥,改善LPS誘導(dǎo)的小鼠抑郁樣行為。(4)和正常組相比,FCPR03對賽拉嗪和氯胺酮聯(lián)合麻醉后小鼠翻正反射恢復(fù)時間沒有統(tǒng)計學差異,且不引起比格犬的嘔吐反應(yīng),提示FCPR03具有較低的致嘔吐潛能。結(jié)論:FCPR03能夠上調(diào)cAMP/PKA/CREB信號通路,降低p38和JNK的磷酸化水平,抑制NF-κB的活化,抑制炎癥因子的釋放,降低中樞的神經(jīng)炎癥,進而改善LPS誘導(dǎo)的小鼠抑郁樣行為。同時,FCPR03具有較低的致嘔吐潛能,提示FCPR03是一個潛在的抗抑郁候選藥物。
[Abstract]:Objective: depression is caused by many factors, with sustained low mood affective disorders as the main clinical features, is one of the major health problems of psychological. In recent years, with the development of modern life rhythm speeding up, increasing social pressure, depression incidence is increasing year by year. Many studies suggest that the inflammatory process and the incidence of central depression are closely related, but more and more studies show that inflammation plays an important role in the occurrence and development of depression, between depression and central inflammation have a close relationship. A large number of studies show that PDE4 inhibitors have significant anti-inflammatory effect in vivo, at the same time can also produce antidepressant effect through upregulation of cAMP/PKA/CREB signaling pathway, however, because of the serious adverse reaction of nausea and vomiting, limiting its clinical. The further application of.FCPR03 is the independent research group design and synthesis of novel PDE4 inhibitors, the experimental results show that the high selectivity of PDE4. The nerve inflammation hypothesis of depression based on LPS to establish the animal model of depression induced by inflammation of the subject, to evaluate the improving effect of FCPR03 on mice depression like behavior induced by LPS, and the LPS BV-2 induced the activation of microglia as inflammation model in vitro of FCPR03 nerve, anti neuroinflammatory effect and its mechanism of study can provide a theoretical basis for the improvement of drugs by inflammation induced depression. Methods: (1) the depression model of behavioral despair tail suspension and forced swimming tests to explore the antidepressant effect of FCPR03. (2) establish the LPS induced depression like behavior in the animal model of mice after intraperitoneal injection of 1.2mg/kg LPS as a mice model of depression induced by inflammation, Study on the effect evaluation of FCPR03 on LPS induced depression like behaviors of mice and its related mechanism. (3) BV-2 induced microglial activation in vitro by nerve inflammation model simulated 1 g/mlLPS, anti inflammation effect evaluation of FCPR03 nerve in vitro. (4) through the observation of ketamine / xylazine induced righting reflex disappeared from the recovery time and beagle dogs were used to evaluate the FCPR03 induced vomiting induced vomiting potential. Results: (1) compared with the normal group, different doses of FCPR03 mice by intraperitoneal injection of 30 min, there were no statistical differences in the open field test score level and vertical score; and in the tail suspension and forced swimming test in the real time of mice decreased significantly, showed that FCPR03 has a potential antidepressant effect. (2) in mice after intraperitoneal injection of 1.2mg/kgLPS24h, body weight of mice was significantly reduced, at the same time in the tail suspension and forced swimming tests in mice Significant increase in real time, sucrose preference is significantly reduced, and 7 consecutive days after intragastric administration of FCPR03 in mice, can reduce behavior in real time, increase in sucrose preference, suggesting that FCPR03 can improve the LPS induced depression like behavior. (3) further research found that FCPR03 may be mediated by cAMP/PKA/CREB signaling pathway, increased expression of cortex and hippocampus in BDNF, p38 and JNK decreased the phosphorylation level of NF-, inhibiting the activation of NF kappa B, thereby inhibiting the release of inflammatory cytokines, suppression of central nerve inflammation, improve LPS induced rat depression like behavior. (4) compared with the normal group. FCPR03 of xylazine and ketamine combined anesthesia after righting reflex recovery time was not statistically significant, and does not lead to vomiting in beagle dogs, suggesting that FCPR03 has lower potential induced vomiting. Conclusion: FCPR03 can increase cAMP/PKA/CREB signaling pathway P38 and JNK, decreased the phosphorylation level of NF-, inhibiting the activation of NF kappa B, inhibiting the release of inflammatory cytokines, reducing inflammation of the central nerve, and improve the LPS induced depression like behavior. At the same time, FCPR03 has lower induced vomiting potential, suggesting that FCPR03 is a potential anti depression drug candidate.

【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R965

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相關(guān)期刊論文 前1條

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本文編號：1465614