蛋白质组学及相关分析技术研究曲马多诱导斑马鱼脑氧化应激和依赖性潜力的关键蛋白质
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摘要
盐酸曲马多(Tramadol hydrochloride，TH)作为一种非麻醉性中枢镇痛药，已经成为世界范围内最广泛使用的处方药。关于曲马多在脊椎动物中的积极作用的报导曾经一直占据主导地位，包括缓解中度至重度疼痛、抗抑郁、抗炎和免疫刺激作用、排尿控制、降低糖尿病症体内的血糖浓度等。然而，近年来曲马多滥用中毒、不良反应和依赖性的市场监测报告和临床案例却日益增多，而滥用相关的神经毒性、功能障碍和依赖性潜力的细胞和分子水平机理的研究报道却极少。因而，迫切需要从分子和细胞水平对曲马多滥用可能造成的依赖性潜力和神经毒性等进行微观分析。
本论文选用斑马鱼(Danio rerio)为研究对象，从行为学角度观察和统计发现，曲马多急性处理增加鱼对氧的需求量和对富氧的水体表层的偏好性，从而显著增大表层的鱼平均分布密度。与毒麻类强镇痛药—杜冷丁阳性对照组相比同样存在显著差异，曲马多处理组的这些异常现象不仅出现的更迅速，且持续时间更长(整个过程长达6 h)，并伴随着鱼运动活力的下降，属于斑马鱼对曲马多特有的异常行为和生理反应。含曲马多饲料的长期投喂，则会造成斑马鱼体重和脑重量平均值的下降。这些独特异常的生理反应，使斑马鱼成为研究曲马多药物毒性和药物依赖性分子机理理想的动物模型。
与其他阿片类药物类似，曲马多引起SOD酶活力下降和脂质过氧化物含量的增加，表现出氧化强化剂特性；而慢性诱导过程中的抗氧化酶活性变化规律表明，斑马鱼对曲马多的氧化毒性产生一定的适应性和耐受性。气相色谱质谱联用分析技术(GC／MS)跟踪检测，单剂量肌注给药后的鱼脑、眼、鳃、心、肝、肠、肌等7种组织中曲马多分布和清除情况；而绘制的原药含量随时间变化趋势图则显示出，曲马多在鱼脑内经历了一个快速分布和缓慢清除的过程。进一步从鱼脑组织中检测出两种主要去甲基代谢物，即O-去甲基曲马多(M1)和N-去甲基曲马多(M2)，其中M2的含量明显高于M1，为主要去甲基代谢物。因而肌注给药途径和GC／MS分析技术，适合于研究曲马多在鱼体内的分布、清除、代谢和药效，尤其是神经毒性机理；进一步结合SOD酶活性和MDA含量测定结果，即可以评估脑组织氧化应激程度，还可以为合适的给药剂量的选择和后续的蛋白质组学技术筛选和鉴定关键蛋白质的实验样品的准备提供科学的参考价值。
蛋白质组学是目前从组织器官中筛选与鉴定差异蛋白质的最佳分析技术之一。作者建立了一套适用于筛选和鉴定斑马鱼脑组织中的差异蛋白质的蛋白质组学研究方案。尤其是半定量双向凝胶电泳技术的建立和质谱鉴定前的样品准备中人血清转铁蛋白、白蛋白、铁蛋白等蛋白添加剂或石蜡油、甘油、凡士林等黏合剂作为肽质量指纹质谱鉴定的辅助增强剂的发现，都有效地提高了差异蛋白鉴定的灵敏度和可信度。曲马多诱导差异表达的30个蛋白质斑点经鉴定后，归为13种蛋白，其中14-3-3蛋白、肌酸激酶(CK BB)、ATP合成酶(H+转运，线粒体F1复合体，beta亚基)和微管蛋白等在不同的凝胶位置，分别检出3、3、4和11种亚型；按蛋白功能分为六大类：细胞骨架、能量代谢、信号传导、突触功能、蛋白降解和修饰、钙信号调节。多数蛋白是参与氧化应激或氧化应激相关疾病发病机理的重要蛋白，例如：14-3-3蛋白，CK BB，泛素羧基端水解酶-L1(UCHL-1)，ATP合成酶，突触体相关蛋白(SNAP)，微管蛋白，肌动蛋白等；而蛋白：醛缩酶C，ATP合成酶，CK BB，丙酮酸脱氢酶激酶，UCHL-1，14-3-3蛋白，dynamin1，SNAP，微管蛋白，肌动蛋白等则属于多种药物依赖相关的共同蛋白。同时也发现了一些尚未报导的新蛋白，例如：钙信号调节相关蛋白novel protein similar tovertebrate EF hand calcium binding protein 2，结构相关蛋白novel intermediatefilament protein，similar to centrosomal protein 110 kDa。曲马多同已知的依赖性药物一样主要通过三种普遍认可的途径引发神经毒性，即能量代谢、氧化应激和蛋白降解、修饰。
Western blotting和酶活性分析表明，曲马多慢性诱导上调14-3-3 epsilon蛋白表达量，和抑制酶缩酶和肌酸激酶(能量系统中的两种重要酶)活性，且此类影响一直维持到撤药后两周仍十分显著。相关结果进一步验证了蛋白质组学技术筛选和鉴定的曲马多诱导的差异蛋白的可信度。曲马多慢性诱导引起多种与氧化应激和能量代谢密切相关的重要蛋白质的表达量下调，而这些蛋白的差异表达都直接或间接的涉及线粒体结构和功能的改变。曲马多慢性处理后的线粒体超微结构观察显示，线粒体分布紊乱，数目显著下降，基质变稀，电子密度下降，出现肿胀、空泡样，线粒体嵴数目减少、断裂甚至是缺失等一系列与结构和功能障碍密切相关的形态学变化。
基于行为学、药物代谢、免疫印迹、酶学测定和超微结构观察等多种手段辅助下的蛋白质组学及其相关技术筛选和鉴定曲马多诱导的斑马鱼脑组织氧化应激关键蛋白的结果，从细胞和分子水平揭示了曲马多长期滥用导致脑组织氧化应激、线粒体损伤和蛋白修饰或降解相关的神经毒性，以及引起能量系统失衡、细胞骨架破坏等，且很可能存在依赖性潜力；本论文的研究结果也为曲马多在世界范围内广泛使用可能存在的神经毒性和依赖性潜力等药物安全性方面的问题提供了新的富有意义的证据，而建立起来的结合了多种研究手段的蛋白质组学方法、以及鉴定出的多种关键蛋白质，在其他药物的神经毒性和依赖性潜力评估方面同样具有重要的运用价值。
Tramadol hydrochloride(TH),an atypical centrally acting opioid analgesic,hasbecome the most prescribed drug worldwide.Previous reports predominantly havefocused on the numerous positive response of TH in vertebrates,including analgesiafor moderate to severe pain;antidepressant,anti-inflammatory,andimmunostimulatory effects,micturition control;an ability to lower glucose indiabetics and so on.However,the data on the increase in TH related fatalities,adversereactions,and the drug addiction presented in recent years have been obtained frompostmarketing surveillance and case reports,unfortunately,cellular and molecularmechanisms involved in neurotoxicity,dysfunction and addiction potential afterchronic and abused TH administration are not well documented.These issueshighlight the need to assess the addiction potential and neurotoxicity of TH abuse atthe cellular and molecular levels.
In this thesis,zebrafish(Danio rerio) was chosen as experimental object.Theresults,from the perspective of behavior observation and statistical,showed thatoxygen demand and preference of oxygen-rich surface water layer were heightened infish,thus significantly increased the mean distribution density of fish in surface layer,by a TH stimulus.Compared with those in pethidine hydrochloride(more effectiveanalgesic) positive control group,the abnormal behavior was even more significant,which was observed to emerge much faster,and last much longer(the whole processup to 6 h).Moreover,it was also accompanied by a significant reduction in activity.The phenomenon was belongs to TH specific abnormal behavior and physiologicalresponse in zebrafish.Body and brain mean weight loss in zebrafish,after long-termreceiving food containing TH.Specific physiological responses to TH exposure,makes zebrafish a favorable animal model for experimental studies of the mechanismsof TH toxicity and drug addiction.
With the similar prooxidant properties with other opioids,TH was shown to inducea decrease in the activity of SOD,and an increase in lipoperoxide.Based on the regulation ofantioxidant enzyme activity,zebrafish had developed certain adaptabilityand tolerance to the oxidative toxicity during the chronic TH administration.Aftersingle IM injection,Gas Chromatography-Mass Spectrometry(GC/MS) trackinganalysis was used to examine the diffusion and elimination of the parent compound in7 kinds of tissue,including brain,eyes,gill,heart,liver,gut,and muscle.Regulationof TH content vs.time demonstrated a rapid drug diffusion and longer eliminationprocess in fish brain.Two principal metabolites O-desmethyl(M1) and N-desmethyl(M2) TH were detected in the brain tissue,and content of M2 was significantly higherthan that of M1,as the main desmethyl metabolite in zebrafish.Methods of IMinjection and GC/MS tracking analysis,could be well introduced to the study on THabsorption,distribution,clearance,metabolism and drug effect,especially themechanism of neurotoxicity in zebrafish,and their combination with the assays ofSOD enzyme activity and MDA content,could be used to assessment of degree ofoxidative stress in brain,but also to offer scientific reference values for theappropriate doses selection and experimental samples preparation for the follow-upscreening and identification of the key proteins by proteomics technologies.
Proteomics has recently become one of the best analytical techniques to screen andidentify the differential proteins in tissues and organs.One practical research strategyhad been set up to screen and identify differential proteins in zebrafish brain byproteomics,especially in the establishment of semi-quantitative 2D-PAGE andintroduction of two strategies for sample preparation for peptide mass fingerprintinganalysis,namely usages of protein intensifiers(including human serum transferrin,albumin,ferritin),and mineral oil-,glycerol-,Vaseline-coated targets.All of thesestrategies led to effective improvement of identification of differential proteins insensitivity and reliability.A total of 30 TH induced differential protein spots wereidentified,and classifed into 13 categories of proteins,in which various subtypes of14-3-3 proteins,creatine kinase,ATP synthase(H+ transporting mitochondrial F1complex beta polypeptide),and tubulin were identified at the separated location onthe gel for 3,3,4,and l l times respectively.The TH responsive proteins identifiedwere involved in cytoskeletal system,energy metabolism,signal transduction, synaptic function,protein modification or degradation,and calcium signal regulator.Most of them have functions in oxidative stress or oxidative stress related diseasespathogenesis,including 14-3-3 proteins,creatine kinase BB(CK BB),ubiquitincarboxy-terminal hydrolase L-1(UCHL-1),ATP synthase,synaptosome-associatedprotein(SNAP),tubulin,actin.Furthermore,proteins including aldolase C,ATPsynthase,CK BB,pyruvate dehydrogenase kinase,UCHL-1,14-3-3 proteins,dynamin 1,SNAP,tubulin and actin,also differentially expressed in proteomics ofknown drug addiction.Meanwhile some other identified proteins have not yet beenreported,such as calcium signal regulation related protein—novel protein similar tovertebrate EF hand calcium binding protein 2,cytoskeletal related protein—novelintermediate filament protein similar to centrosomal protein 110 kDa.Similar toknown addiction drugs,TH induced neurotoxicity in zebrafish brain by three paths,namely energy metabolism,oxidative stress and protein modification or degradation.
Western blotting and enzyme activity assay confirmed the results that chronic THinduced up-regulation of 14-3-3 epsilon peptide,and inhibition of aldolase andcreatine kinase enzyme activity,the two important enzymes in energy metabolism.All effects were still significant after two weeks of TH cessation.Furthermore,allabove results verified the reliability of screening and identification of the differentialproteins by proteomics technologies.Chronic TH treatment induced thedown-regulation of some important proteins involved in oxidative stress and energymetabolism,which directly or indirectly led to the changes of mitochondrial structureand function.Ultrastructureal observation on mitochondria showed series ofmorphological changes in the case of TH exposure,for example,distribution disorder,numeral density decreased significantly,the mitochondrial matrix was cleared,electron density decreased,swelling and vacuolation was observable,meanwhile themitochondria cristae show significant reduction,breakdown and in some cases wereabsent.
Combining multiple methods,including behavior observation,drug metabolismdetection,western blotting,enzymes activity assay,and ultrastructural observation,with proteomics to screen and identify TH-associated key proteins,results suggested the involvement of neurotoxicity evaluated by oxidative stress,mitochondrialdysfunctions,and protein modification or degradation,moreover imbalances ofenergy metabolism,damages of cytoskeletal system in the effects of long-tern THabuse,at the cellular and molecular level.Furthermore,the addiction potential is mostlikely to accompany with chronic and long period exposure to TH.The results of thisthesis also provide meaningful evidence for the safety of TH,including neurotoxicityand addiction potential,as it is widely used throughout the world,and proteomicstechnologies based on a variety of other research methods and the identified keyproteins,also have application value in assessment the neurotoxicity and addictionpotential of other drugs.
本论文选用斑马鱼(Danio rerio)为研究对象，从行为学角度观察和统计发现，曲马多急性处理增加鱼对氧的需求量和对富氧的水体表层的偏好性，从而显著增大表层的鱼平均分布密度。与毒麻类强镇痛药—杜冷丁阳性对照组相比同样存在显著差异，曲马多处理组的这些异常现象不仅出现的更迅速，且持续时间更长(整个过程长达6 h)，并伴随着鱼运动活力的下降，属于斑马鱼对曲马多特有的异常行为和生理反应。含曲马多饲料的长期投喂，则会造成斑马鱼体重和脑重量平均值的下降。这些独特异常的生理反应，使斑马鱼成为研究曲马多药物毒性和药物依赖性分子机理理想的动物模型。
与其他阿片类药物类似，曲马多引起SOD酶活力下降和脂质过氧化物含量的增加，表现出氧化强化剂特性；而慢性诱导过程中的抗氧化酶活性变化规律表明，斑马鱼对曲马多的氧化毒性产生一定的适应性和耐受性。气相色谱质谱联用分析技术(GC／MS)跟踪检测，单剂量肌注给药后的鱼脑、眼、鳃、心、肝、肠、肌等7种组织中曲马多分布和清除情况；而绘制的原药含量随时间变化趋势图则显示出，曲马多在鱼脑内经历了一个快速分布和缓慢清除的过程。进一步从鱼脑组织中检测出两种主要去甲基代谢物，即O-去甲基曲马多(M1)和N-去甲基曲马多(M2)，其中M2的含量明显高于M1，为主要去甲基代谢物。因而肌注给药途径和GC／MS分析技术，适合于研究曲马多在鱼体内的分布、清除、代谢和药效，尤其是神经毒性机理；进一步结合SOD酶活性和MDA含量测定结果，即可以评估脑组织氧化应激程度，还可以为合适的给药剂量的选择和后续的蛋白质组学技术筛选和鉴定关键蛋白质的实验样品的准备提供科学的参考价值。
蛋白质组学是目前从组织器官中筛选与鉴定差异蛋白质的最佳分析技术之一。作者建立了一套适用于筛选和鉴定斑马鱼脑组织中的差异蛋白质的蛋白质组学研究方案。尤其是半定量双向凝胶电泳技术的建立和质谱鉴定前的样品准备中人血清转铁蛋白、白蛋白、铁蛋白等蛋白添加剂或石蜡油、甘油、凡士林等黏合剂作为肽质量指纹质谱鉴定的辅助增强剂的发现，都有效地提高了差异蛋白鉴定的灵敏度和可信度。曲马多诱导差异表达的30个蛋白质斑点经鉴定后，归为13种蛋白，其中14-3-3蛋白、肌酸激酶(CK BB)、ATP合成酶(H+转运，线粒体F1复合体，beta亚基)和微管蛋白等在不同的凝胶位置，分别检出3、3、4和11种亚型；按蛋白功能分为六大类：细胞骨架、能量代谢、信号传导、突触功能、蛋白降解和修饰、钙信号调节。多数蛋白是参与氧化应激或氧化应激相关疾病发病机理的重要蛋白，例如：14-3-3蛋白，CK BB，泛素羧基端水解酶-L1(UCHL-1)，ATP合成酶，突触体相关蛋白(SNAP)，微管蛋白，肌动蛋白等；而蛋白：醛缩酶C，ATP合成酶，CK BB，丙酮酸脱氢酶激酶，UCHL-1，14-3-3蛋白，dynamin1，SNAP，微管蛋白，肌动蛋白等则属于多种药物依赖相关的共同蛋白。同时也发现了一些尚未报导的新蛋白，例如：钙信号调节相关蛋白novel protein similar tovertebrate EF hand calcium binding protein 2，结构相关蛋白novel intermediatefilament protein，similar to centrosomal protein 110 kDa。曲马多同已知的依赖性药物一样主要通过三种普遍认可的途径引发神经毒性，即能量代谢、氧化应激和蛋白降解、修饰。
Western blotting和酶活性分析表明，曲马多慢性诱导上调14-3-3 epsilon蛋白表达量，和抑制酶缩酶和肌酸激酶(能量系统中的两种重要酶)活性，且此类影响一直维持到撤药后两周仍十分显著。相关结果进一步验证了蛋白质组学技术筛选和鉴定的曲马多诱导的差异蛋白的可信度。曲马多慢性诱导引起多种与氧化应激和能量代谢密切相关的重要蛋白质的表达量下调，而这些蛋白的差异表达都直接或间接的涉及线粒体结构和功能的改变。曲马多慢性处理后的线粒体超微结构观察显示，线粒体分布紊乱，数目显著下降，基质变稀，电子密度下降，出现肿胀、空泡样，线粒体嵴数目减少、断裂甚至是缺失等一系列与结构和功能障碍密切相关的形态学变化。
基于行为学、药物代谢、免疫印迹、酶学测定和超微结构观察等多种手段辅助下的蛋白质组学及其相关技术筛选和鉴定曲马多诱导的斑马鱼脑组织氧化应激关键蛋白的结果，从细胞和分子水平揭示了曲马多长期滥用导致脑组织氧化应激、线粒体损伤和蛋白修饰或降解相关的神经毒性，以及引起能量系统失衡、细胞骨架破坏等，且很可能存在依赖性潜力；本论文的研究结果也为曲马多在世界范围内广泛使用可能存在的神经毒性和依赖性潜力等药物安全性方面的问题提供了新的富有意义的证据，而建立起来的结合了多种研究手段的蛋白质组学方法、以及鉴定出的多种关键蛋白质，在其他药物的神经毒性和依赖性潜力评估方面同样具有重要的运用价值。
Tramadol hydrochloride(TH),an atypical centrally acting opioid analgesic,hasbecome the most prescribed drug worldwide.Previous reports predominantly havefocused on the numerous positive response of TH in vertebrates,including analgesiafor moderate to severe pain;antidepressant,anti-inflammatory,andimmunostimulatory effects,micturition control;an ability to lower glucose indiabetics and so on.However,the data on the increase in TH related fatalities,adversereactions,and the drug addiction presented in recent years have been obtained frompostmarketing surveillance and case reports,unfortunately,cellular and molecularmechanisms involved in neurotoxicity,dysfunction and addiction potential afterchronic and abused TH administration are not well documented.These issueshighlight the need to assess the addiction potential and neurotoxicity of TH abuse atthe cellular and molecular levels.
In this thesis,zebrafish(Danio rerio) was chosen as experimental object.Theresults,from the perspective of behavior observation and statistical,showed thatoxygen demand and preference of oxygen-rich surface water layer were heightened infish,thus significantly increased the mean distribution density of fish in surface layer,by a TH stimulus.Compared with those in pethidine hydrochloride(more effectiveanalgesic) positive control group,the abnormal behavior was even more significant,which was observed to emerge much faster,and last much longer(the whole processup to 6 h).Moreover,it was also accompanied by a significant reduction in activity.The phenomenon was belongs to TH specific abnormal behavior and physiologicalresponse in zebrafish.Body and brain mean weight loss in zebrafish,after long-termreceiving food containing TH.Specific physiological responses to TH exposure,makes zebrafish a favorable animal model for experimental studies of the mechanismsof TH toxicity and drug addiction.
With the similar prooxidant properties with other opioids,TH was shown to inducea decrease in the activity of SOD,and an increase in lipoperoxide.Based on the regulation ofantioxidant enzyme activity,zebrafish had developed certain adaptabilityand tolerance to the oxidative toxicity during the chronic TH administration.Aftersingle IM injection,Gas Chromatography-Mass Spectrometry(GC/MS) trackinganalysis was used to examine the diffusion and elimination of the parent compound in7 kinds of tissue,including brain,eyes,gill,heart,liver,gut,and muscle.Regulationof TH content vs.time demonstrated a rapid drug diffusion and longer eliminationprocess in fish brain.Two principal metabolites O-desmethyl(M1) and N-desmethyl(M2) TH were detected in the brain tissue,and content of M2 was significantly higherthan that of M1,as the main desmethyl metabolite in zebrafish.Methods of IMinjection and GC/MS tracking analysis,could be well introduced to the study on THabsorption,distribution,clearance,metabolism and drug effect,especially themechanism of neurotoxicity in zebrafish,and their combination with the assays ofSOD enzyme activity and MDA content,could be used to assessment of degree ofoxidative stress in brain,but also to offer scientific reference values for theappropriate doses selection and experimental samples preparation for the follow-upscreening and identification of the key proteins by proteomics technologies.
Proteomics has recently become one of the best analytical techniques to screen andidentify the differential proteins in tissues and organs.One practical research strategyhad been set up to screen and identify differential proteins in zebrafish brain byproteomics,especially in the establishment of semi-quantitative 2D-PAGE andintroduction of two strategies for sample preparation for peptide mass fingerprintinganalysis,namely usages of protein intensifiers(including human serum transferrin,albumin,ferritin),and mineral oil-,glycerol-,Vaseline-coated targets.All of thesestrategies led to effective improvement of identification of differential proteins insensitivity and reliability.A total of 30 TH induced differential protein spots wereidentified,and classifed into 13 categories of proteins,in which various subtypes of14-3-3 proteins,creatine kinase,ATP synthase(H+ transporting mitochondrial F1complex beta polypeptide),and tubulin were identified at the separated location onthe gel for 3,3,4,and l l times respectively.The TH responsive proteins identifiedwere involved in cytoskeletal system,energy metabolism,signal transduction, synaptic function,protein modification or degradation,and calcium signal regulator.Most of them have functions in oxidative stress or oxidative stress related diseasespathogenesis,including 14-3-3 proteins,creatine kinase BB(CK BB),ubiquitincarboxy-terminal hydrolase L-1(UCHL-1),ATP synthase,synaptosome-associatedprotein(SNAP),tubulin,actin.Furthermore,proteins including aldolase C,ATPsynthase,CK BB,pyruvate dehydrogenase kinase,UCHL-1,14-3-3 proteins,dynamin 1,SNAP,tubulin and actin,also differentially expressed in proteomics ofknown drug addiction.Meanwhile some other identified proteins have not yet beenreported,such as calcium signal regulation related protein—novel protein similar tovertebrate EF hand calcium binding protein 2,cytoskeletal related protein—novelintermediate filament protein similar to centrosomal protein 110 kDa.Similar toknown addiction drugs,TH induced neurotoxicity in zebrafish brain by three paths,namely energy metabolism,oxidative stress and protein modification or degradation.
Western blotting and enzyme activity assay confirmed the results that chronic THinduced up-regulation of 14-3-3 epsilon peptide,and inhibition of aldolase andcreatine kinase enzyme activity,the two important enzymes in energy metabolism.All effects were still significant after two weeks of TH cessation.Furthermore,allabove results verified the reliability of screening and identification of the differentialproteins by proteomics technologies.Chronic TH treatment induced thedown-regulation of some important proteins involved in oxidative stress and energymetabolism,which directly or indirectly led to the changes of mitochondrial structureand function.Ultrastructureal observation on mitochondria showed series ofmorphological changes in the case of TH exposure,for example,distribution disorder,numeral density decreased significantly,the mitochondrial matrix was cleared,electron density decreased,swelling and vacuolation was observable,meanwhile themitochondria cristae show significant reduction,breakdown and in some cases wereabsent.
Combining multiple methods,including behavior observation,drug metabolismdetection,western blotting,enzymes activity assay,and ultrastructural observation,with proteomics to screen and identify TH-associated key proteins,results suggested the involvement of neurotoxicity evaluated by oxidative stress,mitochondrialdysfunctions,and protein modification or degradation,moreover imbalances ofenergy metabolism,damages of cytoskeletal system in the effects of long-tern THabuse,at the cellular and molecular level.Furthermore,the addiction potential is mostlikely to accompany with chronic and long period exposure to TH.The results of thisthesis also provide meaningful evidence for the safety of TH,including neurotoxicityand addiction potential,as it is widely used throughout the world,and proteomicstechnologies based on a variety of other research methods and the identified keyproteins,also have application value in assessment the neurotoxicity and addictionpotential of other drugs.
引文
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