內(nèi)源性大麻素系統(tǒng)在荷瘤應(yīng)激誘發(fā)抑郁中的作用
發(fā)布時間：2018-09-08 13:19
【摘要】：內(nèi)源性大麻素系統(tǒng)(endocannabinoid system,ECS)與應(yīng)激適應(yīng)、情緒調(diào)控等精神功能存在密切關(guān)系。內(nèi)源性大麻素(endocannabinoids,eCBs)花生四烯酸乙醇胺(anandamide,AEA)和花生四烯酸甘油酯(2-arachydonyl glycerol,2-AG),在神經(jīng)沖動下誘導(dǎo)合成、釋放,激動突觸前膜的CB1受體,調(diào)節(jié)突觸可塑性,維持神經(jīng)功能穩(wěn)態(tài)。本課題組前期通過對荷瘤小鼠行為學(xué),海馬基因表達(dá)及腦代謝組學(xué)的研究,發(fā)現(xiàn)外周荷瘤可誘發(fā)小鼠的抑郁表現(xiàn),并導(dǎo)致大腦中與情緒調(diào)控相關(guān)的結(jié)構(gòu)發(fā)生基因水平及代謝水平的改變。研究內(nèi)源性大麻素系統(tǒng)在荷瘤應(yīng)激中的變化,可為腫瘤誘發(fā)抑郁的生物學(xué)機(jī)制提供實驗依據(jù)。本研究主要包括:1.采用替代分析物策略建立LC-MS/MS方法,用穩(wěn)定同位素標(biāo)記的AEA-d4和2-AG-d5替代AEA和2-AG,同時對小鼠血漿和大腦前額葉、海馬及下丘腦的AEA及2-AG定量測定,其線性范圍分別為0.325~32.5ng/mL和11~5500ng/mL。2.采用Western Blot技術(shù)對小鼠大腦上述各腦區(qū)的CB1受體以及大麻素降解酶即脂肪酸胺水解酶(fatty acid amide hydrolase,FAAH)的表達(dá)進(jìn)行分析。3.采用EIA技術(shù)測定小鼠皮質(zhì)酮水平。研究5-HT再攝取抑制劑類(selective serotonin reuptake inhibitors,SSRIs)抗抑郁藥鹽酸氟西汀及新型抗抑郁藥阿戈美拉汀對荷瘤鼠皮質(zhì)酮水平的影響;研究FAAH抑制劑URB597及CB1受體激動劑Win55,212-2對荷瘤小鼠皮質(zhì)酮變化的影響。結(jié)果表明,本研究建立的替代分析物L(fēng)C-MS/MS方法,解決了傳統(tǒng)LC-MS/MS定量方法的內(nèi)源性干擾,操作簡捷,結(jié)果可靠。荷瘤小鼠前額葉、海馬及下丘腦的AEA含量顯著降低,而2-AG含量僅在前額葉顯著降低,在海馬及下丘腦未見明顯變化,血漿的AEA及2-AG含量均無明顯變化。荷瘤小鼠CB1受體及FAAH的表達(dá)僅在海馬有顯著增加,在前額葉及下丘腦無明顯變化。荷瘤小鼠血漿較正常者升高,兩種不同抗抑郁藥均可降低荷瘤鼠升高的血漿皮質(zhì)酮。荷瘤小鼠前額葉、海馬及下丘腦的皮質(zhì)酮均較正常組顯著升高,抑制FAAH活性可有效降低荷瘤鼠的血漿以及上述不同腦區(qū)皮質(zhì)酮的升高。CB1激動劑對荷瘤鼠血漿及不同腦區(qū)的皮質(zhì)酮水平?jīng)]有顯著影響。綜上,荷瘤可導(dǎo)致內(nèi)源性大麻素系統(tǒng)發(fā)生改變,內(nèi)源性大麻素系統(tǒng)可能在荷瘤應(yīng)激及進(jìn)一步誘發(fā)抑郁中發(fā)揮重要作用。抑制大麻素降解對改善荷瘤誘發(fā)的應(yīng)激反應(yīng)具改善作用。
[Abstract]:Endogenous cannabinoid system (endocannabinoid system,ECS) is closely related to stress adaptation, emotional regulation and other mental functions. Endogenous cannabinoid (endocannabinoids,eCBs) arachidonic acid ethanolamine (anandamide,AEA) and arachidonic acid glycerol ester (2-arachydonyl glycerol,2-AG) are induced to synthesize release excite the CB1 receptor of presynaptic membrane regulate synaptic plasticity and maintain neural function homeostasis. Through the study of behavior, hippocampal gene expression and brain metabolism in tumor-bearing mice, our group found that peripheral tumor could induce depression in mice. It also leads to changes in gene level and metabolism level in structures related to emotional regulation. To study the changes of endogenous cannabinoid system in tumor-bearing stress may provide experimental evidence for the biological mechanism of tumor-induced depression. This research mainly includes: 1. The LC-MS/MS method was established by the substitution analysis strategy, and the stable isotope labeled AEA-d4 and 2-AG-d5 were used to replace AEA and 2-AG.The linear ranges of AEA and 2-AG in plasma and prefrontal lobe, hippocampus and hypothalamus of mice were determined by 0.325~32.5ng/mL and 115500ng / ml 路L ~ (-2), respectively. Western Blot technique was used to analyze the expression of CB1 receptor and nip degrading enzyme (fatty acid amide hydrolase,FAAH) in the above brain regions of mice. The level of corticosterone in mice was determined by EIA technique. To study the effects of fluoxetine hydrochloride, a new antidepressant, 5-HT reuptake inhibitor (selective serotonin reuptake inhibitors,SSRIs, and a new antidepressant, acomelatin, on corticosterone levels in tumor-bearing mice, and to study the effects of FAAH inhibitor URB597 and CB1 receptor agonist Win55212-2 on the changes of corticosterone in tumor-bearing mice. The results showed that the LC-MS/MS method, which was established in this study, solved the endogenous interference of the traditional LC-MS/MS quantitative method, and the operation was simple and the results were reliable. The content of AEA in prefrontal lobe, hippocampus and hypothalamus decreased significantly in mice bearing tumor, but the content of 2-AG decreased only in prefrontal lobe, but not in hippocampus and hypothalamus. The contents of AEA and 2-AG in plasma did not change significantly. The expression of CB1 receptor and FAAH was increased only in hippocampus, but not in prefrontal lobe and hypothalamus. The plasma levels of corticosterone in tumor-bearing mice were higher than those in normal mice, and both antidepressants and antidepressants could decrease plasma corticosterone levels in tumor-bearing mice. Corticosterone in prefrontal lobe, hippocampus and hypothalamus of tumor-bearing mice was significantly higher than that of normal group. Inhibition of FAAH activity could effectively reduce the plasma levels of corticosterone in tumor-bearing mice and the elevation of corticosterone in different brain regions. CB1 agonists had no significant effect on the levels of corticosterone in plasma and different brain regions of tumor-bearing mice. The endogenous cannabinoid system may play an important role in tumor-bearing stress and further induced depression. Inhibition of cannabinoid degradation can improve tumor-induced stress response.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R749.4
本文編號：2230636
[Abstract]:Endogenous cannabinoid system (endocannabinoid system,ECS) is closely related to stress adaptation, emotional regulation and other mental functions. Endogenous cannabinoid (endocannabinoids,eCBs) arachidonic acid ethanolamine (anandamide,AEA) and arachidonic acid glycerol ester (2-arachydonyl glycerol,2-AG) are induced to synthesize release excite the CB1 receptor of presynaptic membrane regulate synaptic plasticity and maintain neural function homeostasis. Through the study of behavior, hippocampal gene expression and brain metabolism in tumor-bearing mice, our group found that peripheral tumor could induce depression in mice. It also leads to changes in gene level and metabolism level in structures related to emotional regulation. To study the changes of endogenous cannabinoid system in tumor-bearing stress may provide experimental evidence for the biological mechanism of tumor-induced depression. This research mainly includes: 1. The LC-MS/MS method was established by the substitution analysis strategy, and the stable isotope labeled AEA-d4 and 2-AG-d5 were used to replace AEA and 2-AG.The linear ranges of AEA and 2-AG in plasma and prefrontal lobe, hippocampus and hypothalamus of mice were determined by 0.325~32.5ng/mL and 115500ng / ml 路L ~ (-2), respectively. Western Blot technique was used to analyze the expression of CB1 receptor and nip degrading enzyme (fatty acid amide hydrolase,FAAH) in the above brain regions of mice. The level of corticosterone in mice was determined by EIA technique. To study the effects of fluoxetine hydrochloride, a new antidepressant, 5-HT reuptake inhibitor (selective serotonin reuptake inhibitors,SSRIs, and a new antidepressant, acomelatin, on corticosterone levels in tumor-bearing mice, and to study the effects of FAAH inhibitor URB597 and CB1 receptor agonist Win55212-2 on the changes of corticosterone in tumor-bearing mice. The results showed that the LC-MS/MS method, which was established in this study, solved the endogenous interference of the traditional LC-MS/MS quantitative method, and the operation was simple and the results were reliable. The content of AEA in prefrontal lobe, hippocampus and hypothalamus decreased significantly in mice bearing tumor, but the content of 2-AG decreased only in prefrontal lobe, but not in hippocampus and hypothalamus. The contents of AEA and 2-AG in plasma did not change significantly. The expression of CB1 receptor and FAAH was increased only in hippocampus, but not in prefrontal lobe and hypothalamus. The plasma levels of corticosterone in tumor-bearing mice were higher than those in normal mice, and both antidepressants and antidepressants could decrease plasma corticosterone levels in tumor-bearing mice. Corticosterone in prefrontal lobe, hippocampus and hypothalamus of tumor-bearing mice was significantly higher than that of normal group. Inhibition of FAAH activity could effectively reduce the plasma levels of corticosterone in tumor-bearing mice and the elevation of corticosterone in different brain regions. CB1 agonists had no significant effect on the levels of corticosterone in plasma and different brain regions of tumor-bearing mice. The endogenous cannabinoid system may play an important role in tumor-bearing stress and further induced depression. Inhibition of cannabinoid degradation can improve tumor-induced stress response.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R749.4
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相關(guān)期刊論文 前3條
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