实验性糖尿病性周围神经病发病机制及保护的研究
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摘要
本研究的目的是深入阐明实验性糖尿病性周围神经病(DPN)的发病机制,从而为临床治疗提供更加准确的作用靶点。本研究的实验方法包括:1、采用一次性腹腔注射链脲佐菌素制备DPN大鼠模型;2、实验动物分为两组:正常对照组(NC组)和糖尿病组(DM组),DM组又随机分为5个亚组:DM4W组、DM8W组、DM12W组、干预1组(T1组)、干预2组(T2组);3、应用Meditronic keypoint-4 workstation肌电图仪测定各组大鼠坐骨神经运动及感觉神经传导速度(MNCV和SNCV)和CMAP及SNAP;4、应用激光多普勒血流测定仪(LDF)检测各组大鼠下肢微循环血流量;5、通过HE染色及电镜观察各组大鼠神经内膜毛细血管及坐骨神经的形态学改变;6、应用免疫组织化学的方法分析各组大鼠氧化应激相关因子(VEGF、TNF-α、IL-1、Il-6、NF-κB、p38MAPK、Caspase-3、Bax、Bcl-2)及ET/NO系统(ET-1、ETA受体、ETB受体、iNOS、eNOS、nNOS)的表达变化规律。7、分析各因素在DPN发生发展过程中的作用及相关性。本研究结果发现:1、各组大鼠体重及血糖变化:DM组大鼠较造模前和NC组大鼠体重明显减轻;血糖持续维持在较高水平(>16.7mmol/L),并且没有自发缓解的现象。2、各组大鼠坐骨神经电生理检查结果:与造模前和NC组相比,DM组大鼠从4W开始出现明显的MNCV和SNCV减慢及CMAP和SNAP减低,并且随病程延长而逐渐加重;前列地尔可以明显地改善DM组大鼠坐骨神经的MNCV、SNCV、CMAP、SNAP。3、各组大鼠下肢微循环血流量变化:与造模前和NC组相比,DM组大鼠从2W开始出现微循环血流量明显下降,且随病程进展逐渐加重,12W下降的幅度超过50%;前列地尔可以明显地提高DM组大鼠下肢的微循环血流量。4、各组大鼠坐骨神经形态学改变:①HE染色显示DM组大鼠从4W开始出现神经内膜毛细血管管壁逐渐增厚,管腔不规则,内皮细胞肿胀、变形,随病程延长而逐渐加重;同时也从4W开始出现坐骨神经有髓及无髓神经纤维排列松散,且随病程进展逐渐出现髓鞘变薄、分离、空泡形成,并伴有轴索萎。②电镜显示DM组大鼠从4W开始出现毛细血管内皮增厚,基底膜不清楚,周围有炎细胞浸润;同时有髓神经纤维髓鞘板层薄厚不一、分离或脱落,无髓神经纤维轴索内神经丝减少,线粒体肿胀,粗面内质网扩张,可见髓样小体,且随病程延长而逐渐加重;前列地尔可以明显改善DM组大鼠神经内膜毛细血管和坐骨神经的形态学表现,早期干预优于晚期干预。5、各组大鼠氧化应激相关因子的表达变化:与造模前和NC组相比,DM组大鼠坐骨神经中VEGF、TNF-α、IL-1、NF-κB、p38MAPK、Caspase-3、Bax表达增高,Il-6、Bcl-2表达减少,且随病程延长而逐渐加重;前列地尔可以改善DM组大鼠坐骨神经中VEGF、TNF-α、IL-1、IL-6、NF-κB、p38MAPK、Caspase-3、Bax的表达变化,但是不影响Bcl-2的表达,早期干预优于晚期干预。6、各组大鼠ET/NO系统相关因子的表达变化:NOS主要在轴索表达,与造模前和NC组相比,DM组大鼠坐骨神经中eNOS、iNOS、nNOS表达减少,且随病程延长而逐渐加重;ET-1及其受体生理状态下表达极少,但是病理状态下,在髓鞘的表达明显增多,与造模前和NC组相比,DM组大鼠坐骨神经中ET-1、ETA受体、ETB受体表达增加,且随病程延长而逐渐加重;前列地尔可以增加DM组大鼠坐骨神经中eNOS、iNOS、nNOS的表达,减少ET-1、ETA受体、ETB受体的表达,早期干预优于晚期干预。本研究得出如下结论:1、应用链脲佐菌素腹腔注射可成功建立实验性糖尿病性周围神经病的动物模型。2、DPN大鼠下肢微循环血流改变先于神经传导速度、神经内膜微血管和坐骨神经的形态学改变,微循环血流减低可能是DPN发生的始动因素,是DPN的重要发病机制之一。3、氧化应激相关因子(VEGF、TNF-α、IL-1、Il-6、NF-κB、p38MAPK、Caspase-3、Bax、Bcl-2)参与了DPN的病理生理过程。DPN大鼠下肢微循环血流改变先于氧化应激相关因子的改变,且氧化应激反应的激活又加重了微循环血流障碍。4、DPN大鼠下肢微循环血流改变先于ET/NO系统的变化,而DM时ET/NO系统的激活通过上调ET-1及其受体、下调NOS来影响微循环,参与DPN的发病。
Recently, the incidence of diabetes mellitus (DM) rises in the world. In the present, there are 170 million DM patients all over the world. It is estimated that it will be doubled in 2003 and the new patients mainly will come from the Asian developing countries, such as the People’s Republic of China and India. Diabetic peripheral neuropathy (DPN) is one of the most common microangiopathy complications of DM. The incidence of DPN is about 5%-50%. In American, DPN incidence is up to 32.7% among the DM patients aged over 40 and it will rise up with the advanced course. The pathogenesis of DPN is not very clear. Hence, the studies on the pathogenesis and treatment strategy of DPN have become a very important work of medical researchers.
DPN is induced by multiple causes and complicated mechanisms, which are not clear so far. Presently, there are several theories of DPN’s pathogenesis: metabolism theory, microvascular dysfunction theory, nerve nutrition factors deficiency theory, immunity theory, and genetic theory. Recently, it is believed that microvascular and metabolic dysfunction play key roles in DPN development and new researches are mainly focused on them. However, the initial factor of DPN development and correlation among related factors are unknown. Hence, our study is designed to observe the simultaneous and consecutive changes on streptozocin-injection rats systematically and all-sidely, which includes electrophysiology, microcirculation blood flow in low extremities, pathological morphology, oxidative stress related factors (VEGF, TNF-α, IL-1, Il-6, NF-κB, p38MAPK, Caspase-3, Bax, Bcl-2), and ET/NO system (ET-1、ETA receptor, ETB receptor, iNOS, eNOS, nNOS). Prostaglandin E1 (PGE1) is used to observe its effects on the DPN rats. The effects and relationships between these factors and DPN and the protective effects of PGE1 are studied from multiple views and in many ways. The purpose of this study is to make further investigation of DPN’s pathogenesis and try to find more accurate target point of treatment for the clinical practice.
Main study methods: 1. Experimental DPN model is made by streptozocin-injection rats. 2. Study groups: Experimental DPN rats are divided into two groups. One is normal control group (NC group) and another is diabetes mellitus group (DM group). DM group is divided into five subgroups: DM 4W group, DM8W group, DM 12W group, Treatment 1 group (T1 group), and Treatment 2 group (T2 group). 3. Motor nerve conduction velocity (MNCV), sensory nerve conduction (SNCV), and compound muscle action potential (CMAP), sensory nerve action potential (SNAP) of sciatic nerve are measured on experimental DPN rats by Meditronic keypoint-4 workstation electromyography. 4. Microcirculation blood flow in lower extremities is measured on experimental DPN rats by Laser Doppler flowmetry (LDF). 5. Morphological changes of nerve inner membrane capillary and sciatic nerve are observed by light microscope with HE dye and by electronmicroscope. 6. Expression of oxidative stress related factors (VEGF、TNF-α、IL-1、Il-6、NF-κB、p38MAPK、Caspase-3、Bax、Bcl-2) and ET/NO system related factors (ET-1、ETA receptor、ETB receptor、iNOS、eNOS、nNOS) are observed by immunohistochemistry methods.
Main study results: 1. Body weight and blood glucose level changes of each group rats: Body weights of DM group rats obviously decrease compared to itself before streptozocin injection or to the NC group rats. Blood glucose level is kept on a high level (>16.7mmol/L) and without spontaneous relief phenomenon. 2. Electrophysiological changes of each group rats: Compared with itself before streptozocin injection or to the NC group rats, MNCV, SNCV and CMAP, SNAP of DM group rats’sciatic nerve begin to decrease markedly since 4W after streptozocin injection. They progress with the advanced DPN course. They can be distinctly improved by PGE1. 3. Microcirculation blood flow changes in low extremities of each group rats: Compared with itself before streptozocin injection or to the NC group rats, microcirculation blood flow of DM group rats starts to decrease sharply since 2W after streptozocin injection. It progresses with the advanced DPN course. Its decrease are up to over 50% when 12W. It is obviously improved by PGE1. 4. Morphological changes of each group rats’sciatic nerve: (1) Since 4W, the vessel walls of nerve inner membrane capillary in DM group rats begins to thick progressively by HE dye method. It also shows irregular and narrowed vessel lumen and swelling, out-of-shape endothelium cells. It progresses with the advanced DPN course. Simultaneously, myelinated and unmyelinated sciatic nerve fiber of DM group rats also start to line loosely. As the course advanced, they gradually show thinner and separated myelin sheath. Vacuolus formation and axon atrophy also can be seen. (2) Through electronmicroscope, it is found in DM groups rats’sciatic nerve with thick capillary endothelium, unclear basement membrane, inflammatory cells infiltration, unequal or separated or drop-off myelin sheath, decreased nerve filament inside axon, swollen mitochondria, expanded rough endoplasmic reticulum. It progresses with the advanced DPN course. All these manifestations can be obviously improved by PGE1 and early treatment is better than late. 5. Oxidative stress related factors expression changes: Compared with itself before streptozocin injection or to the NC group rats, expressions of VEGF、TNF-α、IL-1、NF-κB、p38MAPK、Caspase-3、Bax increase and expressions of Il-6、Bcl-2 decrease in DM group rats sciatic nerve. These expression changes progress with the advanced DPN course. Expression of VEGF、TNF-α、IL-1、IL-6、NF-κB、p38MAPK、Caspase-3、Bax can be distinctly improved by PGE1 and early treatment is better than late. But Bcl-2 expression is not effected by PGE1. 6. ET/NO system related factors expressions changes: NOS mainly expresses inside axon. Compared with itself before streptozocin injection or to the NC group rats, expressions of eNOS、iNOS、nNOS decrease in DM group rats’sciatic nerve. These expression changes progress with the advanced DPN course. Normally, ET-1 and its receptors express little in the rats’sciatic nerve. However, their expressions obviously increase under pathological status. Compared with itself before streptozocin injection or to the NC group rats, expressions of ET-1、ETA receptor、ETB receptor increase. These expression changes progress with the advanced DPN course. These changes can be improved by PGE1 and early treatment is better than late.
Conclusion: 1. Experimental DPN rat model can be successfully established by streptozocin injection. 2. Microcirculation blood flow changes in the lower extremities are earlier than the NCV changes and morphological changes of nerve inner membrane capillary and sciatic nerve. So it is possible that microcirculation blood flow decrease may be the initial factor of DPN development. Mircrocirculation dysfunction is an important pathogenesis of DPN. 3. Oxidative stress related factors (VEGF、TNF-α、IL-1、Il-6、NF-κB、p38MAPK、Caspase-3、Bax、Bcl-2) take part in the pathophysiological changes of DPN. On the one hand, microcirculation blood flow changes in the lower extremities are earlier than the oxidative stress related factors changes. On the other hand, activations of oxidative stress related factors aggravate microcirculation dysfunction. 4. In DPN rats, microcirculation blood flow changes in the lower extremities are earlier than the ET/NO system related factors changes. In DM, through up-regulated ET-1 and its receptors expression and down-regulated NOS expression, ET/NO system is activated to effect microcirculation and to take part in the DPN development.
Through the observations of effects and relationships of oxidative stress related factors, ET-1 and its receptors, and NOS during the DPN development and progress, our study makes further investigations of DPN’s pathogenesis. Our study makes it clear that microcirculation is the initial factor of DPN. Hence, our results provide more accurate target point of treatment in the clinical practice.
Recently, the incidence of diabetes mellitus (DM) rises in the world. In the present, there are 170 million DM patients all over the world. It is estimated that it will be doubled in 2003 and the new patients mainly will come from the Asian developing countries, such as the People’s Republic of China and India. Diabetic peripheral neuropathy (DPN) is one of the most common microangiopathy complications of DM. The incidence of DPN is about 5%-50%. In American, DPN incidence is up to 32.7% among the DM patients aged over 40 and it will rise up with the advanced course. The pathogenesis of DPN is not very clear. Hence, the studies on the pathogenesis and treatment strategy of DPN have become a very important work of medical researchers.
DPN is induced by multiple causes and complicated mechanisms, which are not clear so far. Presently, there are several theories of DPN’s pathogenesis: metabolism theory, microvascular dysfunction theory, nerve nutrition factors deficiency theory, immunity theory, and genetic theory. Recently, it is believed that microvascular and metabolic dysfunction play key roles in DPN development and new researches are mainly focused on them. However, the initial factor of DPN development and correlation among related factors are unknown. Hence, our study is designed to observe the simultaneous and consecutive changes on streptozocin-injection rats systematically and all-sidely, which includes electrophysiology, microcirculation blood flow in low extremities, pathological morphology, oxidative stress related factors (VEGF, TNF-α, IL-1, Il-6, NF-κB, p38MAPK, Caspase-3, Bax, Bcl-2), and ET/NO system (ET-1、ETA receptor, ETB receptor, iNOS, eNOS, nNOS). Prostaglandin E1 (PGE1) is used to observe its effects on the DPN rats. The effects and relationships between these factors and DPN and the protective effects of PGE1 are studied from multiple views and in many ways. The purpose of this study is to make further investigation of DPN’s pathogenesis and try to find more accurate target point of treatment for the clinical practice.
Main study methods: 1. Experimental DPN model is made by streptozocin-injection rats. 2. Study groups: Experimental DPN rats are divided into two groups. One is normal control group (NC group) and another is diabetes mellitus group (DM group). DM group is divided into five subgroups: DM 4W group, DM8W group, DM 12W group, Treatment 1 group (T1 group), and Treatment 2 group (T2 group). 3. Motor nerve conduction velocity (MNCV), sensory nerve conduction (SNCV), and compound muscle action potential (CMAP), sensory nerve action potential (SNAP) of sciatic nerve are measured on experimental DPN rats by Meditronic keypoint-4 workstation electromyography. 4. Microcirculation blood flow in lower extremities is measured on experimental DPN rats by Laser Doppler flowmetry (LDF). 5. Morphological changes of nerve inner membrane capillary and sciatic nerve are observed by light microscope with HE dye and by electronmicroscope. 6. Expression of oxidative stress related factors (VEGF、TNF-α、IL-1、Il-6、NF-κB、p38MAPK、Caspase-3、Bax、Bcl-2) and ET/NO system related factors (ET-1、ETA receptor、ETB receptor、iNOS、eNOS、nNOS) are observed by immunohistochemistry methods.
Main study results: 1. Body weight and blood glucose level changes of each group rats: Body weights of DM group rats obviously decrease compared to itself before streptozocin injection or to the NC group rats. Blood glucose level is kept on a high level (>16.7mmol/L) and without spontaneous relief phenomenon. 2. Electrophysiological changes of each group rats: Compared with itself before streptozocin injection or to the NC group rats, MNCV, SNCV and CMAP, SNAP of DM group rats’sciatic nerve begin to decrease markedly since 4W after streptozocin injection. They progress with the advanced DPN course. They can be distinctly improved by PGE1. 3. Microcirculation blood flow changes in low extremities of each group rats: Compared with itself before streptozocin injection or to the NC group rats, microcirculation blood flow of DM group rats starts to decrease sharply since 2W after streptozocin injection. It progresses with the advanced DPN course. Its decrease are up to over 50% when 12W. It is obviously improved by PGE1. 4. Morphological changes of each group rats’sciatic nerve: (1) Since 4W, the vessel walls of nerve inner membrane capillary in DM group rats begins to thick progressively by HE dye method. It also shows irregular and narrowed vessel lumen and swelling, out-of-shape endothelium cells. It progresses with the advanced DPN course. Simultaneously, myelinated and unmyelinated sciatic nerve fiber of DM group rats also start to line loosely. As the course advanced, they gradually show thinner and separated myelin sheath. Vacuolus formation and axon atrophy also can be seen. (2) Through electronmicroscope, it is found in DM groups rats’sciatic nerve with thick capillary endothelium, unclear basement membrane, inflammatory cells infiltration, unequal or separated or drop-off myelin sheath, decreased nerve filament inside axon, swollen mitochondria, expanded rough endoplasmic reticulum. It progresses with the advanced DPN course. All these manifestations can be obviously improved by PGE1 and early treatment is better than late. 5. Oxidative stress related factors expression changes: Compared with itself before streptozocin injection or to the NC group rats, expressions of VEGF、TNF-α、IL-1、NF-κB、p38MAPK、Caspase-3、Bax increase and expressions of Il-6、Bcl-2 decrease in DM group rats sciatic nerve. These expression changes progress with the advanced DPN course. Expression of VEGF、TNF-α、IL-1、IL-6、NF-κB、p38MAPK、Caspase-3、Bax can be distinctly improved by PGE1 and early treatment is better than late. But Bcl-2 expression is not effected by PGE1. 6. ET/NO system related factors expressions changes: NOS mainly expresses inside axon. Compared with itself before streptozocin injection or to the NC group rats, expressions of eNOS、iNOS、nNOS decrease in DM group rats’sciatic nerve. These expression changes progress with the advanced DPN course. Normally, ET-1 and its receptors express little in the rats’sciatic nerve. However, their expressions obviously increase under pathological status. Compared with itself before streptozocin injection or to the NC group rats, expressions of ET-1、ETA receptor、ETB receptor increase. These expression changes progress with the advanced DPN course. These changes can be improved by PGE1 and early treatment is better than late.
Conclusion: 1. Experimental DPN rat model can be successfully established by streptozocin injection. 2. Microcirculation blood flow changes in the lower extremities are earlier than the NCV changes and morphological changes of nerve inner membrane capillary and sciatic nerve. So it is possible that microcirculation blood flow decrease may be the initial factor of DPN development. Mircrocirculation dysfunction is an important pathogenesis of DPN. 3. Oxidative stress related factors (VEGF、TNF-α、IL-1、Il-6、NF-κB、p38MAPK、Caspase-3、Bax、Bcl-2) take part in the pathophysiological changes of DPN. On the one hand, microcirculation blood flow changes in the lower extremities are earlier than the oxidative stress related factors changes. On the other hand, activations of oxidative stress related factors aggravate microcirculation dysfunction. 4. In DPN rats, microcirculation blood flow changes in the lower extremities are earlier than the ET/NO system related factors changes. In DM, through up-regulated ET-1 and its receptors expression and down-regulated NOS expression, ET/NO system is activated to effect microcirculation and to take part in the DPN development.
Through the observations of effects and relationships of oxidative stress related factors, ET-1 and its receptors, and NOS during the DPN development and progress, our study makes further investigations of DPN’s pathogenesis. Our study makes it clear that microcirculation is the initial factor of DPN. Hence, our results provide more accurate target point of treatment in the clinical practice.
引文
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