本文選題：辛伐他汀 + 奧氮平��； 參考：《西南大學(xué)》2017年碩士論文

【摘要】：背景:精神分裂癥是一類多發(fā)于青少年的重性精神病。青少年一旦患有此類疾病,須長(zhǎng)期或終生服用抗精神病藥物。而奧氮平作為常用的二代抗精神病藥物之一,是現(xiàn)下被廣泛應(yīng)用于治療精神分裂癥的藥物。與第一代抗精神病藥物相比,它對(duì)腦中的5-HT與DA受體均有影響,對(duì)精神分裂癥及各種性狀的精神病都有一定的治療效果。但值得關(guān)注的是,長(zhǎng)期服用奧氮平會(huì)導(dǎo)致嚴(yán)重的與代謝相關(guān)的副作用疾病的發(fā)生例如肥胖,高血脂,胰島素抵抗與高血糖等。這些副作用的發(fā)生會(huì)嚴(yán)重影響患者的生活質(zhì)量,也可能使患者特別是青少年患者對(duì)奧氮平的治療效果失去信心。但奧氮平引起的代謝方面的副作用機(jī)制尚未完全弄清。研究發(fā)現(xiàn)奧氮平可以使體內(nèi)重要的產(chǎn)熱器官——棕色脂肪的活性降低,產(chǎn)熱水平下降,使棕色脂肪的形態(tài)趨近于白色脂肪。棕色脂肪(Brown adipose tissue,BAT)是體內(nèi)一種極其重要的能量代謝的器官,可以通過非顫栗而產(chǎn)生熱量。哺乳動(dòng)物體內(nèi)均有棕色脂肪,且嬰幼兒時(shí)期的棕色脂肪遠(yuǎn)多于成年時(shí)期。因此,幼年機(jī)體的棕色脂肪也是常用的實(shí)驗(yàn)對(duì)象之一。提高棕色脂肪的產(chǎn)熱活性,可以促進(jìn)體內(nèi)能量代謝,使體重下降,并改善血脂血糖異常。其細(xì)胞中線粒體內(nèi)膜上的解偶聯(lián)蛋白-1(Uncoupling protein-1,UCP1)是棕色脂肪特異性產(chǎn)熱蛋白,且在棕色脂肪中高表達(dá),并且UCP1蛋白可將化學(xué)能轉(zhuǎn)化為熱能釋放。除了UCP1,棕色脂肪細(xì)胞中的過氧化物酶體增殖體激活受體γ共激活子α(Peroxisome-proliferator-activated receptor-γco-activator-1α,PGC-1α),過氧化物酶體增殖體激活受體γ(Peroxisome-proliferator-activated receptorγ,PPARγ)以及含PR結(jié)構(gòu)域的蛋白16(PR domain-containing 16,PRDM16)等基因的表達(dá)水平也與產(chǎn)熱活性相關(guān)。而下丘腦的阿片促黑色素原(Proopiomelanocortin,POMC)基因與腦干的酪氨酸羥化酶(Tyrosine hydroxylase,TH)基因的表達(dá)水平的變化也會(huì)影響棕色脂肪的產(chǎn)熱活性的變化。以辛伐他汀(Simvastatin)為代表的他汀類藥物,作為一線降脂藥物,增加血清膽固醇的消除,改善血脂異常癥狀,控制心血管疾病與高血脂患者體重。雖然辛伐他汀在糖脂代謝方面的研究已日漸清晰,但在能量代謝方面特別是與棕色脂肪的作用方面卻鮮有報(bào)道。因此,辛伐他汀是否可以提高棕色脂肪的活性用于改善代謝異常是值得研究的。目的:辛伐他汀可以控制高脂攝食肥胖模型的體重增長(zhǎng),降低血脂血糖水平并改善胰島素的敏感性等。但辛伐他汀是否能激活棕色脂肪產(chǎn)熱活性來(lái)干預(yù)奧氮平引起的體重增長(zhǎng)與代謝失衡尚未有報(bào)道。本研究選擇斷奶幼鼠模擬幼年機(jī)體的代謝功能,通過檢測(cè)辛伐他汀對(duì)奧氮平給藥后大鼠的體重、攝食、血脂血糖、自發(fā)活動(dòng)與棕色脂肪活性等方面變化的影響來(lái)研究辛伐他汀對(duì)于奧氮平引起的體重增長(zhǎng)及代謝異常的干預(yù)功能。方法:1.選擇36只斷奶雌性幼鼠(體重:45-55 g),并將它們隨機(jī)分配為兩個(gè)組(n=18),并分別給予3.0 mg/kg/day奧氮平(t.i.d.)與空白糖丸連續(xù)14天,期間每?jī)商鞕z測(cè)大鼠體重、攝食、肛溫變化。藥物處理14天后,檢測(cè)血漿TG、TC與空腹血糖值。2.將上述大鼠分為四組:空白組隨機(jī)平均分為空白對(duì)照組與辛伐他汀組(10.0 mg/kg/day),奧氮平組隨機(jī)平均分為奧氮平組(3.0 mg/kg/day,t.i.d.)與聯(lián)合給藥組(奧氮平:3.0 mg/kg/day,t.i.d.,辛伐他汀:10.0 mg/kg/day),繼續(xù)給藥35天,每?jī)商鞕z測(cè)大鼠體重、攝食、肛溫變化;3.在聯(lián)合給藥第30天時(shí),進(jìn)行大鼠曠場(chǎng)實(shí)驗(yàn)。將大鼠放入黑色的開口盒中(50×50×50 cm3),普通攝影機(jī)跟蹤拍攝大鼠活動(dòng),每只大鼠拍攝25分鐘,并用Noldus Ethovision分析拍攝的大鼠活動(dòng)錄像分析大鼠的平均速率與總距離來(lái)反映大鼠的自發(fā)活動(dòng)的變化;4.辛伐他汀與奧氮平聯(lián)合給藥中期(第20天)與動(dòng)物實(shí)驗(yàn)結(jié)束時(shí),測(cè)血漿TG、TC與空腹血糖值;在動(dòng)物實(shí)驗(yàn)結(jié)束后檢測(cè)棕色脂肪與白色脂肪的重量;將棕色脂肪進(jìn)行冷凍切片并進(jìn)行油紅染色;5.采用RT-qPCR及Western blotting檢測(cè)棕色脂肪產(chǎn)熱相關(guān)基因與下丘腦和腦干能量代謝相關(guān)基因的mRNA與蛋白表達(dá)水平。結(jié)果:1.奧氮平/辛伐他汀對(duì)大鼠體重與攝食的影響奧氮平單獨(dú)給藥兩周后,奧氮平給藥大鼠的體重明顯高于空白對(duì)照組(99.5±5.7 g vs.79.5±4.5 g,p0.05);與空白對(duì)照組相比,奧氮平增加大鼠的攝食量(40.2±3.6 g vs.33.5g±2.5 g,p0.05);聯(lián)合給藥5周后,辛伐他汀與奧氮平聯(lián)合用藥的大鼠體重與單獨(dú)喂食奧氮平組相比(205.0±11.1 g vs.233.5±10.6 g,p0.05)明顯下降;與空白對(duì)照組相比,辛伐他汀不影響大鼠攝食量(p0.05)。2.辛伐他汀降低奧氮平給藥大鼠的血脂血糖值根據(jù)前兩周奧氮平單獨(dú)給藥后大鼠空腹血漿甘油三酯、膽固醇與血糖值的檢測(cè)可知,奧氮平組的甘油三酯(1.02±0.06 mmol/L vs.0.73±0.02 mmol/L,p0.01)、總膽固醇值(2.40±0.04 mmol/L vs.2.28±0.03 mmol/L,p0.05)與血糖值(7.74±0.13mmol/L vs.7.39±0.11 mmol/L,p0.05)明顯高于空白對(duì)照組。聯(lián)合給藥中期(第20天)檢測(cè)表明,聯(lián)合給藥的血脂血糖值與奧氮平單獨(dú)給藥組相比均有明顯下降(p0.05)。聯(lián)合給藥35天后,奧氮平與辛伐他汀聯(lián)合給藥組的甘油三酯(0.84±0.03mmol/L vs.1.27±0.04 mmol/L,p0.01)、總膽固醇值(2.43±0.05 mmol/L vs.2.74±0.06mmol/L,p0.01)與血糖值(7.47±0.03 mmol/L vs.7.95±0.18 mmol/L,p0.01)明顯低于奧氮平組。辛伐他汀組的甘油三酯(0.59±0.06 mmol/L vs.0.85±0.06 mmol/L,p0.05)與總膽固醇值(2.22±0.10 mmol/L vs.2.45±0.03 mmol/L,p0.05)低于空白對(duì)照,但血糖值與空白對(duì)照相比無(wú)明顯差別(p0.05)。大鼠體重增長(zhǎng)值與總膽固醇值呈顯著性正相關(guān)(r=0.458,p0.01)。3.奧氮平/辛伐他汀對(duì)大鼠自發(fā)活動(dòng)的影響奧氮平給藥大鼠的總距離低于空白對(duì)照組(4091.3±200.6 cm vs.4998.3±157.6 cm,p0.05)且平均速率也低于空白對(duì)照組(2.7±0.1 cm/s vs.3.3±0.1 cm/s,p0.05)。但辛伐他汀對(duì)于奧大鼠的總距離與平均速率的影響并不明顯(both p0.05)。4.奧氮平/辛伐他汀對(duì)大鼠產(chǎn)熱活動(dòng)的影響奧氮平單獨(dú)給藥組的大鼠體溫與空白對(duì)照組相比下降明顯(37.41±0.03℃vs.37.64±0.02℃,p0.01)。辛伐他汀與奧氮平聯(lián)合給藥5周后,與空白對(duì)照組相比,辛伐他汀對(duì)大鼠體溫的調(diào)節(jié)不明顯,但在聯(lián)合給藥后期(第26天后),體溫相比于奧氮平單獨(dú)給藥組有上升趨勢(shì),但沒有出現(xiàn)顯著性差異(p0.05)。5.奧氮平/辛伐他汀對(duì)大鼠脂肪堆積與棕色脂肪形態(tài)的影響奧氮平作用后,大鼠的產(chǎn)熱活動(dòng)下降,辛伐他汀促進(jìn)產(chǎn)熱活動(dòng)的增加,進(jìn)而我們對(duì)大鼠體內(nèi)重要調(diào)節(jié)產(chǎn)熱的器官——棕色脂肪和白色脂肪進(jìn)行研究。相較空白對(duì)照組,奧氮平組的白色脂肪積累明顯增加(7.30±0.58 g vs.6.14±0.18 g,p0.05)。聯(lián)合給藥組比奧氮平組的白色脂肪積累明顯減少(5.67±0.39 g vs.7.30±0.58 g,p0.05)。聯(lián)合給藥組的棕色脂肪比于奧氮平組有明顯增加(0.69±0.04g vs.0.59±0.06 g,p0.05)。另外,根據(jù)棕色脂肪切片油紅染色可知,奧氮平使棕色脂肪的脂滴變大,但辛伐他汀與奧氮平聯(lián)合給藥組的脂滴大小與空白對(duì)照組無(wú)明顯變化。6.奧氮平/辛伐他汀對(duì)大鼠棕色脂肪產(chǎn)熱相關(guān)基因mRNA與蛋白水平的影響奧氮平組相比于空白對(duì)照組,UCP1的轉(zhuǎn)錄水平顯著下調(diào)了~44%(p0.05),PGC-1α下調(diào)了~40%(p0.05)而PPARγ下調(diào)了~55%(p0.05)。相比于奧氮平組,奧氮平與辛伐他汀聯(lián)合給藥組可以上調(diào)UCP1的基因轉(zhuǎn)錄水平(144%±14%vs.56%±11%,p0.01)。聯(lián)合給藥組在PGC-1α的轉(zhuǎn)錄水平上相比于奧氮平組也有明顯提升(103%±13%vs.56%±11%,p0.05)。辛伐他汀聯(lián)合給藥組與奧氮平單獨(dú)給藥組相比,PPARγ的轉(zhuǎn)錄水平明顯上調(diào)(75%±14%vs.45%±6%,p0.05)。而辛伐他汀組PRDM16的轉(zhuǎn)錄水平相比于空白對(duì)照組相比有上調(diào)(141%±11%vs.100%±22%,p0.05)。與空白對(duì)照組相比,UCP1與PGC-1α在奧氮平組中的蛋白表達(dá)量分別顯著下調(diào)了~29%(p0.01)與~25%(p0.05)。奧氮平與辛伐他汀聯(lián)合給藥組的UCP1蛋白表達(dá)水平相比于奧氮平組顯著上升(86%±6%vs.71%±5%,p0.05)。UCP1蛋白表達(dá)水平與大鼠總膽固醇呈顯著性負(fù)相關(guān)(r=-0.484,p0.01)。7.奧氮平/辛伐他汀對(duì)大鼠POMC與TH基因的m RNA水平的影響與空白對(duì)照組相比,下丘腦的POMC與腦干TH在奧氮平的作用下分別降低了~36%(p0.05)與~45%(p0.05),辛伐他汀使POMC的表達(dá)水平顯著上升了~99%(p0.01)。聯(lián)合給藥組與奧氮平組相比,TH轉(zhuǎn)錄水平有明顯上升(108%±9%vs.55%±14%,p0.05)。結(jié)論:奧氮平使大鼠體重增長(zhǎng)明顯,糖脂代謝與能量代謝失衡。辛伐他汀不僅可以調(diào)節(jié)血脂血糖水平,還能通過提高棕色脂肪的活性改善奧氮平引起的體重增長(zhǎng)與代謝異常。相關(guān)性分析顯示,辛伐他汀的降血脂作用可能與激活棕色脂肪相關(guān)。這些結(jié)果為臨床上治療二代抗精分藥物所引起的副作用疾病提供一個(gè)潛在思路與方案。
[Abstract]:Background: schizophrenia is a class of severe psychosis that occurs frequently in adolescents. Once a teenager is suffering from this disease, antipsychotics must be taken for a long time or a lifetime. Olanzapine, one of the two generation antipsychotic drugs commonly used, is widely used in the treatment of schizophrenia. Compared with the first generation of antipsychotic drugs, It has an effect on both 5-HT and DA receptors in the brain, and has a certain therapeutic effect on schizophrenia and all kinds of psychosis. But it is worth noting that olanzapine may lead to severe metabolic associated side effects such as obesity, hyperlipidemia, Isle resistance and hyperglycemia. It can seriously affect the quality of life of the patient and may also lose confidence in the treatment effect of olanzapine, especially in young patients. However, the metabolic side effects of olanzapine have not been fully understood. The brown fat (Brown adipose tissue, BAT) is an extremely important energy metabolic organ in the body that produces heat through non tremor. There are brown fat in mammals, and the brown fat of infants is far more than in adulthood. It is also one of the commonly used experiments. To improve the thermal activity of brown fat, it can promote energy metabolism in the body, reduce body weight, and improve blood glucose and blood glucose abnormality. The uncoupling protein -1 (Uncoupling protein-1, UCP1) on the mitochondrial inner membrane of the cells is a brown fat specific thermoprotein, and is highly expressed in brown fat, and UCP1 Protein can convert chemical energy into heat energy release. In addition to UCP1, peroxisome proliferators in brown adipocytes activate receptor gamma co activator alpha (Peroxisome-proliferator-activated receptor- gamma co-activator-1 alpha, PGC-1 alpha), peroxisome proliferator activated receptor gamma (Peroxisome-proliferator-activated receptor gamma, PPAR gamma). The expression level of protein 16 (PR domain-containing 16, PRDM16), including the PR domain, is also related to the thermal activity, and the changes in the expression level of the Proopiomelanocortin, POMC and Tyrosine hydroxylase, TH in the hypothalamus also affect the heat production of brown fat. Changes in activity. The statins, represented by simvastatin (Simvastatin), serve as a first-line lipid-lowering drug, increase the elimination of serum cholesterol, improve dyslipidemia and control the body weight of patients with cardiovascular disease and hyperlipidemia. Although the study of simvastatin in glycolipid metabolism is increasingly clear, it is especially in energy metabolism. There are few reports on the effect of brown fat. Therefore, it is worth studying whether simvastatin can improve the activity of brown fat to improve metabolic abnormalities. The effect of activating the thermal activity of brown fat to interfere with the body weight growth and metabolic imbalance caused by olanzapine has not been reported. This study selected the young rats of weaning to simulate the metabolic function of the young body, and the effects of simvastatin on the body weight, feeding, blood lipid, blood glucose, self activity and brown fat activity after olanzapine administration. To study the intervention function of simvastatin on the body weight growth and metabolic abnormalities caused by olanzapine. Methods: 1. selected 36 weanling female young rats (weight: 45-55 g), and randomly assigned them to two groups (n=18), and were given 3 mg/kg/day olanzapine (t.i.d.) and blank pills for 14 days, and the weight of rats was detected every two days, feeding, 14 days after the treatment, the plasma TG, TC and fasting blood glucose.2. were divided into four groups. The blank group was randomly divided into blank control group and simvastatin group (10 mg/kg/day). The olanzapine group was randomly divided into olanzapine group (3 mg/kg/day, t.i.d.) and combined administration group (olanzapine: 3 mg/kg/day, t.i.d., octyl. Statins: 10 mg/kg/day), continue to give medicine for 35 days, test rats weight, feeding, and anus temperature changes every two days. 3. in thirtieth days of combined administration, the rat field experiment was carried out. Rats were put into the black open box (50 x 50 * 50 cm3), the ordinary camera tracked the rats' activity, each rat was photographed for 25 minutes, and used Noldus Ethovision to analyze and shoot. The rat activity video was used to analyze the average rate and the total distance of rats to reflect the changes in the spontaneous activity of rats; 4. in the mid-term (Twentieth days) administration of the combined administration of simvastatin and olanzapine, the plasma TG, TC, and fasting blood glucose were measured, and the weight of brown fat and white fat was detected after the end of the animal experiment; and the brown fat was added into the rat. Frozen section and oil red staining; 5. RT-qPCR and Western blotting were used to detect the mRNA and protein expression level of the genes related to the heat production related to the brown fat and the energy metabolism of the hypothalamus and brain stem. Results: 1. olanzapine / simvastatin on the influence of oranzapine on the weight and feeding of rats for two weeks, olanzapine was administered to rats The weight of the rats was significantly higher than that in the blank control group (99.5 + 5.7 g vs.79.5 + 4.5 g, P0.05), and olanzapine increased the intake of rats (40.2 + 3.6 g vs.33.5g + 2.5 g, P0.05), compared with the blank control group; the body weight of the rats combined with the combined administration of simvastatin and olanzapine was compared with the olanzapine group (205 + 11.1 g vs.233.5 + 10.6) after 5 weeks of combined administration G, P0.05) decreased significantly. Compared with the blank control group, simvastatin did not affect the diet of rats (P0.05).2. Simvastatin to reduce the blood lipid of olanzapine in rats. The triglycerides (1.02 + 0.06 mmol) of the olanzapine group were detected in the fasting plasma triglycerides of the rats after olanzapine alone. /L vs.0.73 + 0.02 mmol/L, P0.01), the total cholesterol (2.40 + 0.04 mmol/L vs.2.28 + 0.03 mmol/L, P0.05) and blood glucose (7.74 + 0.13mmol/L vs.7.39 + 0.11 mmol/L, P0.05) were significantly higher than that in the blank control group. The combined administration of the medium-term (Twentieth days) test showed that the blood lipids and blood glucose levels of the combined administration were significantly lower than that of olanzapine alone. (P0.05). After 35 days of combined administration, the triglyceride (0.84 + 0.03mmol/L vs.1.27 + 0.04 mmol/L, P0.01) of olanzapine and simvastatin, total cholesterol (2.43 + 0.05 mmol/L vs.2.74 + 0.06mmol/L, P0.01) and blood glucose (7.47 + 0.03 mmol/L vs.7.95 + 0.18 mmol/L) were significantly lower than that of olanzapine group. The glycerol of simvastatin group was three. The value of the ester (0.59 + 0.06 mmol/L vs.0.85 + 0.06 mmol/L, P0.05) and total cholesterol (2.22 + 0.10 mmol/L vs.2.45 + 0.03 mmol/L, P0.05) was lower than that of the blank control, but there was no significant difference between the blood sugar and the blank (P0.05). The weight growth value of the rats was significantly positively correlated with the total cholesterol (r=0.458, P0.01).3. olanzapine / simvastatin to rats The total distance of olanzapine in rats was lower than that in the blank control group (4091.3 + 200.6 cm vs.4998.3 + 157.6 cm, P0.05) and the average rate was lower than that in the blank control group (2.7 + 0.1 cm/s vs.3.3 + 0.1 cm/s, P0.05). But the effect of simvastatin on the total distance and average rate of the rats was not obvious (both P0.05).4. olanzapine The effect of simvastatin on the heat production in rats was significantly lower than that in the blank control group (37.41 + 0.03 vs.37.64 + 0.02, P0.01). After 5 weeks of combined administration of simvastatin and olanzapine, the regulation of simvastatin on the body temperature of rats was not obvious, but in the later period of the combined Administration ( Twenty-sixth days later), the body temperature was higher than that of olanzapine alone, but there was no significant difference (P0.05) the effect of olanzapine / simvastatin on the fat accumulation and the shape of brown fat in rats. After the effect of olanzapine, the heat production of rats decreased, and simvastatin promoted the increase of heat production, and then we weighed the rats' body weight. The white fat accumulation in the olanzapine group was significantly increased (7.30 + 0.58 g vs.6.14 + 0.18 g, P0.05), compared with the blank control group. The white fat accumulation in the combined administration group was significantly reduced (5.67 + 0.39 g vs.7.30 + 0.58 g, P0.05). The brown fat accumulation in the combined administration group was brown. There was a significant increase in fat ratio in the olanzapine group (0.69 + 0.04g vs.0.59 + 0.06 g, P0.05). In addition, according to brown fat red staining, olanzapine made the fat droplets of brown fat larger, but the size of the lipid droplets of the combined administration of simvastatin and olanzapine had no significant changes in the brown fat of.6. olanzapine / simvastatin in the control group. Compared with the control group, the transcriptional level of UCP1 was significantly reduced by ~44% (P0.05), PGC-1 alpha was down regulated by ~40% (P0.05) and PPAR gamma lowered ~55% (P0.05). Compared to olanzapine group, the combined administration of olanzapine and simvastatin could increase the UCP1 gene transcriptional level (144% + 14%vs). .56% + 11%, P0.01). Compared with olanzapine group at the level of PGC-1 alpha, the combined administration group was also significantly increased (103% + 13%vs.56% + 11%, P0.05). The transcriptional level of PPAR gamma in the combined administration of simvastatin group was significantly up (75% + 14%vs.45% + 6%, P0.05) compared with the olanzapine group alone, while the transcriptional level of the simvastatin group was compared with that of the simvastatin group. Compared with the blank control group, the protein expression of UCP1 and PGC-1 alpha in olanzapine group was significantly reduced by ~29% (P0.01) and ~25% (P0.05), compared with the blank control group. The level of UCP1 protein expression in the combined administration of olanzapine and simvastatin group was significantly higher than that in olanzapine group (86% + 6%vs.71% + 5%, P). 0.05) the expression level of.UCP1 protein was significantly negatively correlated with rat total cholesterol (r=-0.484, P0.01). The effect of.7. olanzapine / simvastatin on the m RNA level of POMC and TH genes in rats was compared with that of the blank control group. The hypothalamic POMC and brainstem TH decreased respectively under the action of olanzapine. The expression level of TH was significantly increased by ~99% (P0.01). Compared with olanzapine group, the TH transcriptional level increased significantly (108% + 9%vs.55% + 14%, P0.05). Conclusion olanzapine could increase the weight growth of rats and the imbalance of glucose and lipid metabolism and energy metabolism. Improving the body weight growth and metabolic abnormalities caused by olanzapine. Correlation analysis shows that the action of simvastatin may be associated with the activation of brown fat. These results provide a potential idea and scheme for the clinical treatment of side effects caused by the two generation of antiseminal drugs.
【學(xué)位授予單位】：西南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R965

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本文編號(hào)：2059822