【摘要】：甲基苯丙胺(methamphetamine, METH),屬于苯丙胺類中樞神經(jīng)系統(tǒng)興奮劑,外觀為純白色結(jié)晶體,俗稱“冰毒”。因制作成本低廉、起效快、作用時(shí)間持久,濫用率逐年增長并趨向低齡化,是聯(lián)合國精神藥品公約明令管制的精神藥物。METH成癮已成為亟待解決的全球性問題。METH成癮是一種反復(fù)服用METH而引起的慢性、復(fù)發(fā)性腦疾病,主要特點(diǎn)是強(qiáng)迫性覓藥、強(qiáng)烈的渴求心理以及中斷用藥后出現(xiàn)戒斷癥狀。長期使用會(huì)引起機(jī)體內(nèi)神經(jīng)元產(chǎn)生異常的代償性適應(yīng),導(dǎo)致耐受、敏化、依賴及復(fù)吸等癥狀。 中腦邊緣多巴胺系統(tǒng),即腹側(cè)被蓋區(qū)(Ventral Tegmental Area, VTA)及其投射區(qū)伏隔核(nucleus accumbens, NAc)、前額葉皮質(zhì)(prefrontal cortex, PFC)等其他腦區(qū)共同構(gòu)成的區(qū)域,與多數(shù)成癮藥物相關(guān),是強(qiáng)迫覓藥和復(fù)吸行為的重要的神經(jīng)環(huán)路。該回路改變可產(chǎn)生強(qiáng)化效應(yīng)、記憶、與渴求相關(guān)聯(lián)的條件反應(yīng)以及戒斷癥狀中的恐懼、焦慮等情緒反應(yīng)。另外,由VTA/NAc/Hippocampus構(gòu)成的強(qiáng)化學(xué)習(xí)記憶回路的激活在METH成癮及復(fù)吸中發(fā)揮重要作用。METH選擇性地作用于這部分腦區(qū),促進(jìn)多巴胺(dopamine, DA)j釋放,引起機(jī)體發(fā)生一系列的適應(yīng)性變化。METH成癮所涉及的信號(hào)通路主要有多巴胺D1受體介導(dǎo)的腺苷酸環(huán)化酶(adenylate cyclase, AC)及其下游環(huán)磷酸腺苷(Cyclic Adenosine monophosphate, cAMP)通路與多巴胺D2受體介導(dǎo)的phosphatidyl inositol3kinase, PI3K/Akt/Glycogen synthase kinase-3β,GSK-3通路,在METH引起的神經(jīng)元結(jié)構(gòu)和功能適應(yīng)性改變的過程中,cAMP反應(yīng)元件結(jié)合蛋白(cAMP response element binding protein, CREB), ΔFosB蛋白和細(xì)胞周期依賴蛋白激酶5(Cyclin-depdent kinase5, Cdk5)起到重要的調(diào)節(jié)作用,但確切的分子機(jī)制尚未闡明。 METH成癮及毒性機(jī)制與氧化應(yīng)激相關(guān)。METH會(huì)引起腦內(nèi)谷胱甘肽、過氧化氫酶等水平降低,脂質(zhì)過氧化物和蛋白羰基的增加；引起DA、5-羥色胺等神經(jīng)遞質(zhì)的氧化；許多與成癮藥物相關(guān)的分子(如：fos/Jun、鈣調(diào)激酶、NF-κB和CREB等)對(duì)神經(jīng)元內(nèi)的氧化還原狀態(tài)敏感。與藥物成癮引起的突觸可塑性變化相關(guān)的長時(shí)程增強(qiáng)(long-term potentiation, LTP)也受機(jī)體的氧化還原狀態(tài)的調(diào)節(jié),進(jìn)入胞內(nèi)的METH通過破壞神經(jīng)元氧化還原平衡,導(dǎo)致氧化應(yīng)激,促使DNA、蛋白質(zhì)等的損傷,從而加劇多巴胺能神經(jīng)元凋亡。已有研究證實(shí),抗氧化劑能緩解藥物成癮的發(fā)生。這些現(xiàn)象提示我們：維持機(jī)體氧化還原平衡可能干預(yù)METH成癮。 硫氧還蛋白(thioredoxin, Trx)是一種重要的氧化還原應(yīng)答蛋白,具有高度保守的氧化還原活性位點(diǎn)：-Cys-Gly-Pro-Cys-(CGPC)。Trx、NADPH和硫氧還蛋白還原酶(thioredoxinreductase, TrxR)組成的Trx還原系統(tǒng),在維持細(xì)胞內(nèi)的氧化還原平衡方面起重要調(diào)節(jié)作用,Trx具有多種生物活性,包括調(diào)節(jié)多種轉(zhuǎn)錄因子的活性,如激活蛋白1(activator protein-1, AP-1)、NF-κB、CREB等,促神經(jīng)突觸生長,調(diào)控細(xì)胞周期、抗凋亡、抗炎等。因此,我們認(rèn)為Trx是中樞神經(jīng)系統(tǒng)疾病預(yù)防或治療的重要靶點(diǎn)。已有研究證明替普瑞酮(Geranylgeranylacetone, GGA)、神經(jīng)妥樂和蘿卜硫素等多種藥物都可以誘導(dǎo)Trx-1的表達(dá)。本論文選擇GGA作為Trx-1的誘導(dǎo)物,因?yàn)?GGA具有親脂性,能夠透過血腦屏障,更有效地作用于腦區(qū);并且,已有研究報(bào)道：GGA具有保護(hù)神經(jīng)免于帕金森病毒性物的損害作用；可以緩解嗎啡引起的條件位置偏愛及戒斷癥狀。 基于METH成癮及毒性作用機(jī)理與Trx-1的生物學(xué)功能,本論文提出三個(gè)假設(shè)：Trx-1參與了METH的作用過程,Trx-1誘導(dǎo)物GGA可以抵抗METH成癮,Trx-1誘導(dǎo)物GGA可以抵抗METH引起的神經(jīng)元凋亡以及肝臟腎臟損傷。 本論文的研究結(jié)果如下： (1)明確Trx-1參與了METH作用過程。本論文采用多巴胺能神經(jīng)元模型——大鼠腎上腺嗜鉻細(xì)胞瘤細(xì)胞(1at pheochromocytoma tumor cell line, PC12)作為研究細(xì)胞,首先,用濃度分別為0.5、1.0、2.0、4.0mM的METH刺激PC12細(xì)胞,通過MTT分析、LDH釋放分析檢測細(xì)胞存活率及損傷程度,結(jié)果發(fā)現(xiàn),從2.0mM開始,METH抑制了PC12細(xì)胞的存活且引起細(xì)胞損傷。用1mM的METH刺激PC12細(xì)胞1、2、4、12、24h,通過蛋白免疫印跡(Western Blotting)檢測Trx-1表達(dá)水平,結(jié)果發(fā)現(xiàn),在METH作用1h的情況下,Trx-1表達(dá)水平顯著升高,而從12h開始,Trx-1表達(dá)水平明顯降低。由于1mM的METH作用PC12細(xì)胞1h未出現(xiàn)凋亡,此時(shí)Trx-1分子水平已經(jīng)發(fā)生變化。因此,第二章后續(xù)實(shí)驗(yàn)均采用的METH的劑量為1mM,作用時(shí)間為1h。為了證明METH對(duì)Trx-1誘導(dǎo)的分子機(jī)制,本論文分別采用0.5mM的SQ22536(AC的抑制劑)、20μM的LY294002(P13K的抑制劑)、5mM Licl (GSK-3β的抑制劑)預(yù)刺激,結(jié)果發(fā)現(xiàn),只有LY294002降低了METH誘導(dǎo)的Trx-1的表達(dá),說明METH對(duì)Trx-1的誘導(dǎo)通過了PI3K通路,為了進(jìn)一步驗(yàn)證這一結(jié)論,本論文檢測了PI3K的下游分子Akt和GSK-3β的活性,即p-Akt和p-GSK-3β的表達(dá)水平,結(jié)果發(fā)現(xiàn),二者均被激活,從而確定了METH是通過PI3K/Akt信號(hào)通路誘導(dǎo)Trx-1表達(dá)。CREB在METH作用過程中起重要作用,調(diào)節(jié)即可早期蛋白的表達(dá),本論文發(fā)現(xiàn)1mM的METH作用PC12細(xì)胞1h引起了CREB活性升高,且升高的活性能夠被LY294002預(yù)刺激所抑制,說明：METH激活CREB也是通過PI3K/Akt這條信號(hào)通路。為了進(jìn)一步闡明Trx-1與METH作用的關(guān)系,本論文采用SiRNA的方法將Trx-1蛋白表達(dá)降低,并檢測到CREB的活性也明顯降低,說明Trx-1作為上游分子介導(dǎo)了CREB的激活。這些數(shù)據(jù)提示我們,Trx-1確實(shí)參與了METH的作用,且發(fā)揮了重要的調(diào)節(jié)作用。 (2)Trx-1誘導(dǎo)物GGA能夠抵抗METH成癮。本論文采用METH成癮小鼠模型作為研究材料,首先,通過METH慢性給藥(2.5mg/kg,隔天腹腔注射,共8天)構(gòu)建METH成癮小鼠模型,通過條件性位置偏愛實(shí)驗(yàn)驗(yàn)證其構(gòu)建成功,并檢測了小鼠腦內(nèi)VTA、NAc、PFC及海馬區(qū)相關(guān)分子的變化,結(jié)果顯示,METH慢性給藥引起了VTA和NAc區(qū)ΔAFosB和細(xì)胞周期依賴蛋白激酶5(Cdk5)表達(dá)水平增加,Trx-1表達(dá)水平降低,CREB活性和熱休克蛋白70(heat shock protein70, Hsp70)表達(dá)水平變化不顯著；為了研究Trx-1誘導(dǎo)物GGA對(duì)METH成癮的抵抗作用,本論文給予小鼠GGA預(yù)處理(800mg/kg/d,灌胃8天),之后METH給藥,行為檢測結(jié)果發(fā)現(xiàn),GGA能降低METH急性作用(2.5mg/kg,一次腹腔注射)所引起的小鼠行為能力的增強(qiáng),抑制METH慢性給藥(2.5mg/kg,隔天腹腔注射,共8天)引起的條件性位置偏愛的形成,條件性位置偏愛消退點(diǎn)燃以及行為敏化。METH成癮患者伴有明顯的消瘦,本論文證明了GGA預(yù)處理可以抑制METH慢性給藥造成的體重降低；在分子水平上,GGA恢復(fù)了METH'慢性給藥(2.5mg/kg,隔天腹腔注射,共8天)引起的VTA和NAc區(qū)ΔFosB和Cdk5表達(dá)的增加及Trx-1表達(dá)的降低；降低了METH條件性位置偏愛消退點(diǎn)燃后海馬區(qū)Cdk5表達(dá)的增加。這些數(shù)據(jù)說明,GGA可以抵抗METH所致的位置偏愛及其消退點(diǎn)燃,行為敏化和運(yùn)動(dòng)能力增強(qiáng),這種抵抗作用主要可能是GGA誘導(dǎo)Trx-1的高表達(dá)而實(shí)現(xiàn)的。 (3) Trx-1誘導(dǎo)物GGA能夠抵抗METH引起的神經(jīng)元凋亡和肝臟、腎臟損傷。METH成癮不僅涉及中樞神經(jīng)系統(tǒng)的適應(yīng)性改變,同時(shí)也是機(jī)體對(duì)藥物毒性積累的過程,對(duì)METH成癮患者的尸檢報(bào)告顯示,METH在大腦、肝臟、腎臟中積累最多,且造成的損傷最大,因此,本論文采用PC12細(xì)胞及METH成癮模型小鼠的肝臟、腎臟為研究材料,首先,通過MTT分析檢測到METH(2mM,24h)可引起PC12細(xì)胞存活率明顯下降,且可以被GGA預(yù)刺激(10μM,提前30min)顯著緩解。酪氨酸羥化酶是合成多巴胺過程中的限速酶,被認(rèn)為是多巴胺能神經(jīng)元活性的標(biāo)志,為了進(jìn)一步研究METH對(duì)PC12細(xì)胞的神經(jīng)毒性,本論文還檢測了TH的表達(dá)量,結(jié)果發(fā)現(xiàn),METH (2mM,24h)引起了TH表達(dá)的降低,同樣可以被GGA預(yù)刺激(10μM,提前30min)顯著緩解。其次,檢測了METH處理(2mM,24h)的PC12細(xì)胞pro-caspase酶的表達(dá)量,結(jié)果發(fā)現(xiàn)METH能夠降低pro-caspase-9、pro-caspase-3,而對(duì)pro-caspase-12無明顯作用,說明,METH處理激活了線粒體介導(dǎo)的細(xì)胞凋亡途徑,而pro-caspase-9、pro-caspase-3的降低可以被GGA預(yù)刺激(10μM,提前30min)所緩解。同樣,本論文還檢測了METH慢性給藥(2.5mg/kg,隔天腹腔注射,共8天)后小鼠肝、腎臟pro-caspase酶的表達(dá)量,與PC12細(xì)胞的結(jié)果相一致,GGA預(yù)處理(800mg/kg/d,灌胃8天)抑制了METH所致pro-caspase-9、pro-caspase-3的降低,而pro-caspase-12無明顯變化。更重要的是,無論是PC12細(xì)胞還是METH成癮模型小鼠的肝臟、腎臟,GGA預(yù)處理均能夠逆轉(zhuǎn)METH引起的Trx-1和Hsp70表達(dá)降低。以上數(shù)據(jù)說明,GGA可以抑制METH對(duì)PC12細(xì)胞及小鼠肝臟、腎臟的毒性作用,這種保護(hù)作用是通過對(duì)Trx-1和Hsp70的共誘導(dǎo)而實(shí)現(xiàn)的。 綜上所述,Trx-1與甲基苯丙胺導(dǎo)致的成癮密切相關(guān),硫氧還蛋白誘導(dǎo)物具有抵抗甲基苯丙胺成癮的作用以及抵抗甲基苯丙胺毒性作用。
[Abstract]:Methamphetamine (METH), an amphetamine-type central nervous system stimulant, is a pure white crystal, commonly known as "methamphetamine". METH addiction is a chronic, recurrent brain disease caused by repeated use of METH. It is characterized by compulsive drug seeking, strong craving and withdrawal symptoms after discontinuation of the drug. Long-term use can cause abnormal compensatory adaptation of neurons in the body, resulting in tolerance, sensitization, dependence, and withdrawal. Relapse and other symptoms.
The ventral tegmental area (VTA) and its projection nucleus accumbens (NAc), prefrontal cortex (PFC), together with other brain regions, are associated with most addictive drugs and are important neural circuits for forcing drug seeking and relapse behavior. Additionally, the activation of the reinforcement learning and memory circuit composed of VTA/NAc/Hippocampus plays an important role in the addiction and relapse of MEH. METH selectively acts on this part of the brain to promote dopamine (DA). The major signaling pathways involved in METH addiction include dopamine D1 receptor-mediated adenylate cyclase (AC) and its downstream cyclic adenosine monophosphate (cAMP) pathways and dopamine D2 receptor-mediated phosphatidyl inositol 3 kinase (PI3K). CAMP response element binding protein (CREB), Delta FosB protein and cyclin-depdent kinase 5 (Cdk5) play important roles in the regulation of neuronal structural and functional adaptation induced by METH. The molecular mechanism of cutting has not yet been elucidated.
METH addiction and toxicity are associated with oxidative stress. METH can cause decreased levels of glutathione and catalase, increased lipid peroxides and protein carbonyls in the brain, oxidization of neurotransmitters such as DA, 5-hydroxytryptamine, and many molecules associated with drug addiction (e.g. fos/Jun, calmodulin kinase, NF-kappa B and CREB) in neurons. Long-term potentiation (LTP), which is related to changes in synaptic plasticity induced by drug addiction, is also regulated by the body's redox state. Intracellular METH leads to oxidative stress by disrupting the redox balance of neurons, causing damage to DNA, proteins and so on, thus aggravating dopa. Amine neuron apoptosis. Antioxidants have been shown to alleviate drug addiction. These phenomena suggest that maintaining the body's redox balance may interfere with METH addiction.
Thioredoxin (Trx) is an important redox-responsive protein with highly conserved redox sites: -Cys-Gly-Pro-Cys-(CGPC). Trx, NADPH and thioredoxin reductase (TrxR) constitute a Trx reductive system that plays an important role in maintaining the balance of redox and oxidation in cells. Trx has a variety of biological activities, including regulating the activity of a variety of transcription factors, such as activator protein-1 (AP-1), NF-kappa B, CREB, promoting synaptic growth, regulating cell cycle, anti-apoptosis, anti-inflammation and so on. Therefore, we believe that Trx is an important target for the prevention or treatment of central nervous system diseases. In this study, GGA was selected as the inducer of Trx-1 because of its lipophilicity and its ability to penetrate the blood-brain barrier and act more effectively on the brain region; moreover, it has been reported that GGA can protect nerves from Parkinson's virus. It can relieve the conditioned place preference and withdrawal symptoms induced by morphine.
Based on the mechanism of METH addiction and toxicity and the biological function of Trx-1, three hypotheses are proposed in this paper: Trx-1 participates in the process of METH, Trx-1 inducer GGA can resist METH addiction, Trx-1 inducer GGA can resist METH-induced neuronal apoptosis and liver and kidney injury.
The research results in this paper are as follows:
(1) Trx-1 is involved in the process of METH. In this study, the rat adrenal pheochromocytoma tumor cell line (PC12), a dopaminergic neuron model, was used as the research cell. Firstly, the PC12 cells were stimulated by MTH at concentrations of 0.5, 1.0, 2.0 and 4.0 mM, respectively. The results showed that METH inhibited the survival of PC12 cells from 2.0 mM and caused cell damage. The expression of Trx-1 was detected by Western Blotting at 1,2,4,12,24 h after stimulation with 1 mM METH. The expression of Trx-1 was significantly increased at 1 h after treatment with METH, but from 12 h on. The expression level of Trx-1 was significantly decreased. The molecular level of Trx-1 had changed since 1 mM ETH did not induce apoptosis in PC12 cells for 1 h. Therefore, the dose of METH used in the second chapter was 1 mM and the duration of action was 1 h. In order to prove the molecular mechanism of the induction of Trx-1 by METH, 0.5 mM SQ22536 (AC inhibitor) was used. LY294002 (inhibitor of P13K) and 5mM Licl (inhibitor of GSK-3 beta) pretreatment showed that only LY294002 decreased the expression of Trx-1 induced by METH, indicating that the induction of Trx-1 by METH passed the PI3K pathway. To further verify this conclusion, the activities of Akt and GSK-3 beta downstream molecules of PI3K, i.e. p-Akt and p-GSK-3 beta, were detected. The results showed that both of them were activated, which confirmed that METH could induce Trx-1 expression via PI3K/Akt signaling pathway. CREB played an important role in the process of METH, and regulated the expression of early proteins. In this paper, we found that 1 mM of METH could induce the elevation of CREB activity in PC12 cells for 1 h, and the elevated activity could be preempted by LY294002. In order to further elucidate the relationship between Trx-1 and METH, SiRNA was used to reduce the expression of Trx-1 protein, and the activity of CREB was also significantly decreased, indicating that Trx-1 as an upstream molecule mediated the activation of CREB. Indeed, Trx-1 has played an important role in regulating METH's role.
(2) Trx-1 inducer GGA can resist METH addiction. In this study, METH addiction mice model was used as research materials. First, METH addiction mice model was established by chronic administration of METH (2.5mg/kg, intraperitoneal injection every other day for 8 days). Conditional place preference test was used to verify the success of the model, and VTA, NAc, PFC and hippocampal phase were detected. The results showed that chronic administration of METH increased the expression of AFosB and Cdk5 in VTA and NAc regions, decreased the expression of Trx-1, and had no significant changes in CREB activity and the expression of heat shock protein 70 (Hsp70). In this study, mice were given GGA pretreatment (800mg/kg/d, intragastric administration for 8 days), and then given METH. Behavioral test results showed that GGA could reduce the acute effect of METH (2.5mg/kg, once intraperitoneal injection) induced by the enhancement of behavior in mice, inhibit the chronic administration of METH (2.5mg/kg, intraperitoneal injection every other day, a total of 8 days) induced conditioned place preference. This study demonstrated that GGA pretreatment could inhibit weight loss caused by chronic METH administration; at the molecular level, GGA restored the VTA and NAc FosB and Cdk5 tables induced by chronic METH administration (2.5mg/kg, intraperitoneal injection every other day, for a total of 8 days). These data suggest that GGA can resist METH-induced position preference and its regressive kindling, and enhance behavioral sensitization and motor ability, which may be due to GGA-induced high expression of Trx-1.
(3) Trx-1 inducer GGA can resist neuronal apoptosis and liver and kidney injury induced by METH. METH addiction involves not only the adaptive changes of central nervous system, but also the accumulation of drug toxicity. Autopsy reports of METH addicts showed that METH accumulated most in brain, liver and kidney, and caused the most damage. In this study, we used PC12 cells and the liver and kidney of METH addicted mice as research materials. First, MTT analysis showed that METH (2mM, 24h) could significantly reduce the survival rate of PC12 cells, and could be significantly alleviated by GGA pre-stimulation (10 mu M, 30 min earlier). In order to further study the neurotoxicity of METH on PC12 cells, the expression of TH in PC12 cells was detected. The results showed that the expression of TH was decreased by METH (2mM, 24h) and could also be significantly alleviated by GGA pre-stimulation (10mM, 30min earlier). Secondly, the expression of pro-c in PC12 cells treated with METH (2mM, 24h) was detected. The results showed that METH could decrease the expression of pro-caspase-9, pro-caspase-3, but had no obvious effect on pro-caspase-12, indicating that METH treatment activated the mitochondrial-mediated apoptosis pathway, while the decrease of pro-caspase-9, pro-caspase-3 could be alleviated by GGA pre-stimulation (10 mu M, 30 min earlier). The expression of pro-caspase in liver and kidney of mice after chronic administration (2.5 mg/kg, intraperitoneal injection every other day for 8 days) was consistent with that of PC12 cells. GGA pretreatment (800 mg/kg/d, 8 days after intragastric administration) inhibited the decrease of pro-caspase-9 and pro-caspase-3 induced by METH, while pro-caspase-12 did not change significantly. These data suggest that GGA can inhibit the toxic effects of METH on PC12 cells and mice liver and kidney, and this protective effect is achieved by co-induction of Trx-1 and Hsp70.
In summary, Trx-1 is closely related to methamphetamine-induced addiction, and thioredoxin inducers can resist methamphetamine addiction and methamphetamine toxicity.
【學(xué)位授予單位】：昆明理工大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.64

【共引文獻(xiàn)】

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