轴突及轴突终末变性与再生在C57BL小鼠帕金森病模型中的作用研究
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摘要
帕金森病(Parkinson’s diseas,PD)是一种中老年人常见的中枢神经系统(center nervous system,CNS)退变性疾病,其病理生理特征为黑质多巴胺能(Dopaminergic,DAG)神经元数目明显减少,使黑质-纹状体通路多巴胺(Dopamine,DA)释放减少,纹状体内DA浓度显著降低,而出现一系列运动功能障碍如静止性震颤、运动迟缓、肌僵直、步态异常及植物神经功能障碍。药物及手术治疗可以缓解一些症状,但不能有效逆转或阻滞病情的发展,且均有一定的副作用。虽然该病确切的原因尚不完全明了,但目前研究显示PD的发病与遗传和环境等多种因素相关。基于PD是以纹状体内DA减少为主要表现的CNS变性疾病,除了中脑黑质DAG神经元的死亡以外,黑质向纹状体投射的神经纤维的变性也会引起黑质-纹状体通路(包括内侧前脑束及纹状体内DAG的轴突终末)的异常(见图1 A),但是长期以来,黑质DAG神经元的凋亡被认为是PD的主要病理变化,因此研究重点主要集中于对DAG神经元凋亡机制和治疗、保护的研究,轴突及轴突终末变性被认为是神经元死亡后的伴随产物,对轴突及轴突终末变性的认识和研究则相对缺乏,因此长期未受到重视,尤其是轴突终末“出芽”再生在PD模型小鼠自发恢复中作用的研究,尚未见到相关的报道。随着近年来认识到轴突变性是神经元对外界刺激可控可逆的主动反应,逐渐认识到轴突及轴突终末变性可能是PD发病的起始因素,并且在PD发展过程中发挥着重要作用,越来越多的干预措施被用来延缓或者阻止轴突的变性,为PD发病机制的研究提供了新的思路。已经有多个报道明确在轴突变性被延缓的情况下,PD动物模型的症状得到改善。研究PD模型小鼠自发恢复现象时发现恢复的原因是通过轴突终末“出芽”再生实现的。因此研究PD轴突变性及恢复的机制,并选择具有针对性的治疗方法或保护措施,可能为PD的预防和治疗带来新的策略。
目的1、本实验通过建立MPTP诱导的C57BL小鼠PD急性、亚急性及慢性动物模型,探讨轴突变性在中脑黑质多巴胺能神经元变性中所起的作用,以及轴突变性对纹状体多巴胺含量的影响,判断轴突及轴突终末变性与多巴胺能神经元变性之间的相互关系及发生的先后顺序;2、通过建立急性、亚急性及慢性PD动物自发恢复模型,探讨轴突及轴突终末“出芽”再生在PD动物模型恢复中所起的作用,以及轴突及轴突终末“出芽”再生对纹状体DA含量的影响,判断PD动物模型自发恢复时DAG神经元胞体及轴突、轴突终末的主要形态学改变; 3、通过建立急性、亚急性及慢性PD模型自发恢复后再损伤模型,探讨轴突及轴突终末变性在再损伤中所起的作用及其机制。为PD发病机制及恢复机制的研究、PD的预防、治疗和康复提供实验依据。方法与结果第一部分实验(MPTP诱导C57BL小鼠PD模型多巴胺能神经元及轴突的损伤):大龄C57BL小鼠55只(32-34w),按给与MPTP的剂量、间隔时间及持续时间不同随机分为4组:对照组、急性组、亚急性组和慢性组,依据PD小鼠出现症状的严重程度及行为学检测(包括爬杆实验、游泳实验、悬挂实验及提尾倒立实验)结果,确定PD动物模型临床分期(包括临床前期、临床早期、临床中期及临床晚期)。各组中分别于临床前期、临床早期、临床中期及临床晚期各处死三只模型小鼠,一只行中脑黑质致密部及纹状体免疫组化染色(包括TH染色、FJC染色)观察多巴胺能神经元胞体及纹状体神经纤维、轴突终末的变性、坏死情况;一只进行透射电镜检查中脑黑质多巴胺能神经元胞体及其投射到纹状体的轴突及轴突终末、突触的超微结构变化情况,一只用高效液相色谱仪-液质联用法检测纹状体内DA、HVA及DOPAC的含量。结合小鼠出现PD症状的早晚,动态观察、比较黑质致密部多巴胺能神经元胞体、轴突、树突及其投射到纹状体的轴突、轴突终末、突触等结构那一个先发生变性、坏死,变性的程度及先后顺序。结果:各组模型均先后出现了PD的症状,并逐渐加重;随临床分期的逐渐加重,PD模型小鼠黑质TH-ir神经元数目进行性减少,与对照组比较,临床前期、临床早期、临床中期及临床晚期分别下降29.6%、44.5%、66.7%及78.4%;DA及DOPAC、HVA含量也呈逐渐下降趋势,纹状体内DA含量分别下降为56.3%、71.5%、84.1%及91.3%,模型组TH-ir细胞计数结果及纹状体DA含量与正常对照组比较均有统计学差异(P< 0. 01),纹状体内TH-ir神经纤维积分光密度值进行性下降。MPTP小鼠PD模型不但SNc内TH-ir神经元细胞数目明显减少,而且TH-ir细胞的轴突及树突数目减少及损害程度要严重于细胞数目的减少及损害,神经纤维纤细且短,严重者甚至轴突完全消失。模型组中临床前期及临床早期小鼠的残留DAG神经元细胞轴突表现为轴突变细,长度缩短,粗细不均匀呈串珠样改变,并且走行迂曲,有轴浆运输障碍表现。FJC染色阳性细胞仅出现在MPTP小鼠模型黑质致密部,细胞计数结果是急性模型>亚急性模型>慢性模型,JFC阳性细胞仅保留有变性的细胞体,轴突及树突未显示,仅个别细胞出现残存的轴突根部,提示变性细胞的轴突及树突已先于胞体变性、消失,不能被FJC染色。透射电镜检查结果:在临床前期或临床早期阶段,PD模型黑质内DAG神经元超微结构及细胞器形态均正常的情况下,纹状体内DAG神经元轴突已经出现变性的早期表现,如局部膨大,膨大处线粒体肿胀变形,线粒体嵴不清甚至消失,出现空泡化,轴突局部膨大处神经微管及神经微丝结构紊乱,不连续,有微管解聚表现,提示轴突变性在先,而DAG神经元胞体的变性在后。第二部分实验(MPTP诱导C57BL小鼠PD模型多巴胺能神经元及轴突、轴突终末损伤后的自发恢复):低龄C57BL小鼠55只(6-8w)随机分为对照组、急性组、亚急性组和慢性组。PD动物模型建立成功后观察其行为学有无自发恢复现象,并再次进行行为学测试确定恢复时期的临床分期,分别于各期处死3只小鼠模型,行中脑黑质致密部及纹状体免疫组化染色(包括TH染色、FJC染色)观察多巴胺能神经元胞体及纹状体神经纤维、轴突终末的变性、坏死情况及再生情况; 3只测纹状体DA、HVA及DOPAC的含量; 3只进行透射电镜检查中脑黑质多巴胺能神经元胞体及其投射到纹状体的轴突、轴突终末、突触的超微结构变化情况,并分别与第一部分实验中临床晚期、临床中期、临床早期及临床前期的电镜结果比较,观察黑质的多巴胺能神经元胞体、胞内细胞器及其投射到纹状体的轴突、轴突终末及突触的变化情况,恢复再生情况。结合模型小鼠恢复情况,动态观察、比较SNc内DAG神经元细胞数、胞体、轴突、树突、突触及纹状体TH-ir神经纤维积分光密度值变化情况,观察纹状体DA的含量是否随症状的缓解而逐渐升高,并且观察DA含量的升高与SNc内DAG神经元胞体的恢复及投射到纹状体的轴突、轴突终末的再生有无关系。结果:急性模型及慢性模型组中动物PD症状能达到临床晚期的比率较亚急性要高,急性模型几乎均有自发恢复现象(恢复率100%),恢复的程度也明显高于另外两种模型;慢性模型PD症状比较典型,但该型模型一旦建立成功,自发恢复现象不明现,有逐渐加重的趋势。恢复期虽然PD模型临床分期在好转,纹状体内DA含量随临床分期好转逐渐升高,与对照组比较,从临床晚期到临床前期,恢复率分别为10.7%、35.1%、44.8%和67.5%。但TH-ir细胞数却仍然在逐渐减少,与对照组比较,临床晚期减少76.3%,恢复到临床中期、早期及前期时分别减少78.4%、82.4%和85.2%。PD小鼠模型恢复期纹状体区TH-ir神经纤维积分光密度值随PD模型临床分期的恢复呈逐渐增高趋势(最低是临床晚期的小鼠)。MPTP小鼠PD模型从临床晚期自发恢复到临床前期时TH染色,虽然残存细胞总数少于临床晚期,但胞体增大,饱满,细胞形态恢复到正常的梭形或多角形,胞浆丰富,核仁居中,胞体轴突及树突粗大,数量多,TH-ir纤维密集粗大成束,走行流畅规律,说明胞体及轴突形态明显改善,可能是残存的轴突及轴突终末通过侧支“出芽”方式再生,恢复了正常的直径。小鼠PD模型自发恢复到临床早期及临床前期的FJC染色结果: SNc内仅有少量的FJC阳性细胞,胞体皱缩,体积缩小,形态不规则,排列紊乱,与刚变性死亡的细胞形态基本接近正常细胞形态不同。电镜结果:DAG神经元胞体形态大小恢复,细胞质中细胞器较丰富,可见丰富的粗面内质网、游离核糖体及数量较多的线粒体,脂褐素较少,有自噬泡出现,细胞核大呈卵圆形,核膜清晰完整,皱褶消失;纹状体内突触数量明显增多,且突触的数量恢复先于胞体结构的恢复,线粒体数量增多,形态及结构完整,线粒体嵴明显;纹状体内轴突肿胀及局部膨大均消失,髓鞘及神经微管、神经微丝排列整齐,连续性好,密集,走行自然,未见断裂及缠结,未见到髓鞘松解断裂现象。恢复期中脑黑质内DAG神经元胞体及轴突的超微结构、纹状体内突触数量恢复情况随临床分期的改善而逐渐好转。第三部分实验(MPTP诱导C57BL小鼠PD模型多巴胺能神经元及轴突损伤自发恢复后再损伤):低龄C57BL小鼠(6-8w)35只随机分对照组、急性组、亚急性组及慢性组,注意观察其行为学方面有无自发恢复现象,并再次进行行为学测试确定恢复时期的临床分期。将从临床晚期逐渐自发恢复到临床早期或临床前期的PD模型小鼠于症状稳定后的第10～15天,再次按30mg/kg腹腔注射MPTP一次,建立恢复后再损伤PD模型。观察小鼠的行为学表现,于注射MPTP后第二天开始处死小鼠,一部分行中脑黑质致密部及纹状体免疫组化染色(包括TH染色、FJC染色)观察多巴胺能神经元胞体及纹状体神经纤维、轴突、轴突终末的变性、坏死情况;另外一部分检测纹状体内DA、HVA及DOPAC的含量;另取一只进行透射电镜检查中脑黑质多巴胺能神经元胞体及其投射到纹状体的轴突、轴突终末、突触的超微结构变化情况,并分别与第一部分实验中临床晚期、临床中期、临床早期、临床前期及第二部分实验中恢复期模型小鼠的电镜结果比较,观察黑质的多巴胺能神经元胞体、胞内细胞器及其投射到纹状体的轴突、轴突终末及突触的变化情况,恢复再生情况及再损伤后的改变情况。结果:共有14只小鼠症状发展到临床晚期,其中有8只出现自发恢复趋势,分别恢复至临床前期至临床中期。再次腹腔注射MPTP一次,注射后小鼠的急性毒性反应较第一次注射时明显减轻,但于注射10h后,迅速出现PD晚期的症状,于注射MPTP后3天开始死亡。纹状体内DA、DOPAC、HVA的含量均急剧减少,与对照组比较,DA含量减少94.2%,DOPAC及HVA各下降了85.1%和76.8%;纹状体区TH-ir神经纤维积分光密度值与对照组比较极低;TH染色发现黑质致密部TH阳性细胞极少,仅6.5±0.6,较对照组减少91.9%;轴突及树突不明显,偶可见轴突根部残留较短的突起,TH-ir纤维稀疏,走行紊乱; FJC染色示SNc内仅有少量的阳性细胞,胞体形态仍接近正常细胞的梭形或不规则多角形,提示是刚发生变性坏死的DAG神经元细胞,胞体的基本形态尚存,但未见细胞轴突及树突显影。电镜结果:MPTP小鼠PD模型自发恢复后再损伤时纹状体内DAG神经元细胞的轴突髓鞘崩解,轴突内神经微管及神经微丝结构严重紊乱,数量明显减少,多数已断裂,仅有少量的神经微管连续,有解聚、崩解、断裂现象,变性程度严重;轴突内线粒体变性,线粒体嵴消失,出现崩解现象;纹状体内突触数量明显减少,残存突触结构形态缩小,突触面宽度变窄。结论:1、MPTP所致的C57BL小鼠PD模型轴突变性、树突消失或断裂是黑质多巴胺能神经元变性的早期标志, DAG细胞以“枝叶枯萎”的细胞死亡方式调亡,即首先突触功能丧失,再到远端轴突病理改变,最后导致细胞死亡;2、MPTP诱导的C57BL小鼠PD模型行为学有自发恢复现象,尤其是急性模型,神经元轴突和轴突终末形态及功能恢复可能早于DAG神经元胞体的恢复及DA合成功能的恢复,即轴突形态及功能恢复可能是PD模型自发恢复的前提和基础; 3、MPTP诱导的C57BL小鼠PD模型行为学自发恢复后易被MPTP再损伤,新生轴突及轴突终末的快速变性坏死是自发恢复后再损伤模型的首先和主要病理改变。提示轴突及轴突终末变性与再生在PD的发病及进程中起着十分重要的作用,对研究多巴胺能神经元变性及恢复机制、对PD的预防、治疗、康复策略有重要的启示意义。
Objective The aims were triple. First, we investigated whether the early loss of axon and dendrites of substantia nigra dopaminergic neurons was specific for MPTP-induced Parkinson’s diseas in C57BL mice model (including acute model, subacute model and chronic model), to explore the role of axonal degeneration in the degeneration of substantia nigra dopaminergic neurons as well as the association with the level of dopamine in striatum and conclude the mutual relationship of axonal degeneration and dopaminergic neuron degeneration. As a secondary aim, we investigated whether the phenomenon of spontaneous recovery of MPTP-induced PD mice model (including acute model, subacute model and chronic model) may be relevant to the regenerative sprouting of remained axon. To explore the role of axonal regenerative sprouting in nigrostriatal dopaminergic system of spontaneous recovery of MPTP-induced PD mice model. As well as axonal regenerative sprouting influence for the level of dopamine in striatum and conclude the major changes of morphology in the striatum and substantia nigra of midbrain of spontaneous recovery of MPTP-induced PD mice model. Third, we first raise reinjury of spontaneous recovery of MPTP-induced PD mice model (including acute model, subacute model and chronic model) and probe the role and mechanism of axonal degeneration in reinjury of spontaneous recovery of MPTP-induced PD mice model (including acute model, subacute model and chronic model). We hope provide a new evidence of theory for PD in the pathogenesy, recovery mechanism, prevention, therapeutic avenues and rehabilitation. Methods and results First experiment ( The degeneration of dopaminergic neuron and axon on MPTP-induced Parkinson’s disease in C57BL mice) : The PD models were formed with intraperitoneal injections of MPTP in old C57BL mice, according to dosage of MPTP, intermission time and persistence time, fifty-five old mice random were divided into control group (saline group), acute group, subacute group and chronic group. Then according to severe degree of PD symptoms and results of behavioral test (for example, Pole test, Swim-test, Traction test and Elevated body swing test) to determine clinical stage of animal model (for example, preclinical phase, clinical early phase, clinical intermediate stage and clinical advanced stage. Three mice models were executed and perfused in every group at preclinical phase, clinical early phase, clinical intermediate stage and clinical advanced stage, respectively. One mouse model’s substantia nigra of midbrain and striatum was treated by Tyrosine hydroxylase (TH)-immunocytochemistry and FJC dyeing, to survey the dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. Another one mouse model’s substantia nigra of midbrain and striatum was treated by electron microscope, to survey the ultramicrostructure of the dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. Third model’s DA, DOPAC and HVA contents in the striatum were measured by High performance liquid chromato-graphy and electrochemical detection. We observed the symptoms of PD mice models and recorded the time that symptoms occurrenced sooner and later, such as tremor, rigidity and bradykinesia, then comparison with the morphological changes of DAG neuron body, axon, dendrite, axon terminal and synapse, at last conclude which one first take place degeneration or necrosis. First experiment results: All group models showed a series of motor functional impairment resembling symptoms of PD and the symptoms become more and more serious. The number of TH-ir neurons gradual decreased (29.6% at preclinical phase, 44.5% at clinical early phase, 66.7% at clinical intermediate stage and 78.4% at clinical advanced stage, respectively) compared to age-matched saline-treated animals. As well as the level of dopamine in striatal also gradual fall-off (56.3% at preclinical phae, 71.5% at clinical early phase, 84.1% at clinical intermediate stage and 91.3% at clinical advanced stage, respectively) in comparison with age-matched saline-treated animals. there are significant difference (P< 0.01). The striatal TH-ir fiber optical density value gradually decreased significantly in comparison with age-matched saline-treated animals. Not only the number and striatal dopamine concentration of TH-ir neurons in SNc obviously decreased by a slow, progressive procedure, but also the number of axons and dendrites declines, and the descending degree of the latter are more severe than the former. The axon of remained DAG neurons was thin and short; crudeness or fineness was inequable and showed a string-of-beads or courser circuity, has an appearance of axoplasmic transport disturbance, even the axon has disappeared completely in some remained DAG neurons. Although left the cell bodies intact but caused a striking fragmentation and apparent degeneration of the dendrites. FJC-ir cell ( namely dopaminergic neurodegenerative neuron) only were discovered in SNc of MPTP-induced PD mice models, the number of FJC-ir cell in the acute model exceed the subacute model and the subacute model exceed chronic model. Although FJC-ir cell remained intact cell bodies, but the axon and dendrites were not immunolabeled or very severe damage, only fewer neurons exhibited relic axonal root. These results indicate that early loss of anox and dendrites is a characteristic morphological feature in the suite of events leading to dopaminergic neurons death. Results of transmission electron microscope: under the circumstances of shape of ultramicrostructure and cellular organ in substantia nigra DAG neurons were normal, such as the cellular nucleus was large and orbicular-ovate, the nuclear membrane was clear and integrity, the lipofuscin scattered in the cytoplasm, there were a lot of rough endoplasmic reticulum, free ribosome, Golgi’s body and mitochondria, the axon of DAG neurons in striatum already have appeared an early appearances of degeneration, for example local intumescentia, the mitochondria was swell in intumescentia, the mitochondrial cristae was blurry and even disappearance completely, the vacuolization was found in mitochondria, the structure of neurofilament and neurotubule were disorder and discontinuation in local intumescentia, the microtubule disaggregation was observed in axon. It indicated that the axonal degeneration was earlier than cell body degeneration. Second experiment (The regeneration of dopaminergic neuron and axon on MPTP-induced Parkinson’s disease in C57BL mice): Fifty-five young mice random were divided into control group (saline group), acute group, subacute group and chronic group.we observed the MPTP-induced PD mice model if have a phenomenon spontaneous recovery and again determined the clinical stage during the recovery period by behavioral test. Three mice models were executed and perfused at preclinical phase, clinical early phase, clinical intermediate stage and clinical advanced stage, respectively. Among three PD mice model’s substantia nigra of midbrain and striatum was treated by Tyrosine hydroxylase (TH)-immunocytochemistry and FJC dyeing, to survey the degeneration, necrosis and regeneration of dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. DA, DOPAC and HVA contents in the stiatum were measured in other three PD mice models. the last three PD mice model’s substantia nigra of midbrain and striatum was treated by electron microscope, to survey the ultramicrostructure of the dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal, and in comparison with first part experiment, at last conclude a conclusion if MPTP-induced PD mice model have a phenomenon of spontaneous recovery, whether or not the striatal TH-ir fibers optical density value and DA contents have a gradually increased tendency with the improvement of PD animal model’symptoms. As well as the recovery of PD animal model with relation to regeneration of axon and the sprouting of dopaminergic axonal terminals. Second experiment results: All group MPTP-induced C57BL young mice have a substantial reduction of striatal dopamine level, the TH-ir fibers optical density value and number of TH-ir cell bodies were also markedly reduced after the toxin treatment. The symptoms of PD were observed following MPTP treatment, especially, acute model and chronic model showed more serious symptoms than subacute model. Thereafter, the symptoms of acute and subacute models showed a spontaneous recovery phenomenon within a few weeks after the toxin treatment. Especially acute PD model, the recovery rate almost gets 100%. However, the chronic PD mice were somewhat different from the acute and subacute PD mice, which showed a typical PD symptoms and become more and more serious, only a fewer models showed a slightly recovery. In the the recovery period, the dopamine content in striatum progressively increased significantly (by 10.7% at clinical advanced stage, by 35.1% at clinical intermediate stage, by 44.8% at clinical early phase and by 67.5% at preclinical phase, respectively) in comparison with age-matched saline-treated animals, from clinical advanced stage to preclinical phase onwards, although the number of TH-ir neurons remained fall off , from clinical advanced stage to preclinical phase, the number of TH-ir neurons declined by 76.3%, 78.4%, 82.4% and 85.2% in comparison with age-matched saline-treated animals, respectively. Tyrosine hydroxylase (TH)-immunocytochemistry was employed for the manifestation of the striatal TH-ir fibers and confocal microscopy was used to determine the optical density value of TH-ir fibers in the striatum. During the recovery period, the striatal TH-ir fiber optical density value of MPTP-induced PD model progressively increased from clinical advanced stage to preclinical phase. TH- immunohistochemical analysis showed that although the number of remained TH-ir neurons in stage of recovery was less than clinical advanced stage, but the cell body of TH-ir neurons is large and full, kytoplasm abundant and nucleolus in centre, the morphous of neurons have recovered normal fusiform shape or polygon. The anox and dendritic processes were frequently apparent and intensive and fasciculation in the remained dopaminergic neurons in substantia nigra. These results indicate that MPTP-treated mice have a potential for spontaneous regenerative sprouting in nigrostriatal dopaminergic system. There are a few FJC-ir cell, the FJC-ir cell bodies appeared to shrink, lose cytoplasmic material, and become detached from neighboring cells, the morphous became irregular and disorder, the volume of degenerating neurons became smaller and concentrationer. It is different from normal morphous of cell。Results of transmission electron microscope: The shape of ultramicrostructure and cellular organ in substantia nigra DAG neurons were normal, such as the cellular nucleus was large and orbicular-ovate, the nuclear membrane was clear and integrity, the reductus was disappearance, the lipofuscin was few in the cytoplasm, there were a lot of rough endoplasmic reticulum, free ribosome, Golgi’s body and mitochondria.The number of synapsis increased obviously in the striatum, and the recovery of synaptic quantity preceded the recovery of cell body, The number of mitochondria increased obviously in synapse, it’s shape and structure were integrity. The axonal swell and local intumescentia have already disappeared completely, the neural sheath, neurotubule and neurofilament lined up in order and intensive, the continuity was fine and natural, the neural sheath fragmentation and solution wasn’t observed in the striatum. During the recovery period, the DAG neurons, ultramicrostructure of axon and the synaptic quantity in striatum were more and more advancement with the improvement of symptoms of PD models. Third experiment (The reinjury of the regeneration of dopaminergic neuron and axon on MPTP-induced Parkinson’s disease in C57BL mice): Thirty-five young mice random were divided into control group (saline group), acute group, subacute group and chronic group. We careful observed the MPTP-induced PD mice model if have a phenomenon spontaneous recovery and again determined the clinical stage during the recovery period by behavioral test. Then chose MPTP-induced PD mice model which recovery from clinical advanced stage to preclinical phase and again raised from ten day to fifteen day after stabilization of symptoms. The reinjury PD model was raised by injecting MPTP with a dose 30 mg/kg again. The reinjury PD model were killed on second day. Some reinjury PD mice model’s substantia nigra of midbrain and striatum was treated by Tyrosine hydroxylase (TH)-immunocytochemistry and FJC dyeing, to survey the degeneration, necrosis and regeneration of dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. DA, DOPAC and HVA contents in the stiatum were measured in other reinjury PD mice models, one reinjury PD mouse model’s substantia nigra of midbrain and striatum was treated by electron microscope, to survey the ultramicrostructure and restorative regeneration of the dopaminergic neurons, axon, distal dendrites, striatal TH-ir fibers, axon terminals, cell organ and synapse and in comparison with first part and second experiment results. Third experiment results: fourteen PD mice models advanced to clinical advanced stage, among the total eight PD mice models showed a spontaneous recovery tendency, the degree of recovery from clinical intermediate stage to preclinical phase. When we again injected MPTP (30mg/kg), the acute toxic reaction was light than first injection, but the reinjury PD mice models fast appearanced a symptoms of clinical advanced stage after injecting MPTP ten hours. Some PD models gradually died. We have observed a robust depletion of striatal DA and its metabolite, DOPAC and HVA. the dopamine content in striatum depleted by 94.2%, DOPAC decreased by 85.1% and HVA declined by 76.8% in comparison with age-matched saline-treated animals, the striatal TH-ir fibers optical density value was extreme low in comparison with age-matched saline-treated animals, the number of TH-ir neurons was scanty in SNc, only about 6.5±0.6, The number of dopaminergic neurons in the substantia nigra were declined about 91.9%in comparison with age-matched saline-treated animals. The axons and dendrites of remained DAG neurons were not apparent, occasionally can find a short axonal root in residual processes. The TH-ir fibers were sparseness and courser disorder. FJC-dyeing found only a few FJC-ir cells in SNc, but the cell body of FJC-ir neurons is approximately normocellular figure, such as kytoplasm abundant, fusiform shape or polygon. It indicated that these cells died in a short time. Results of transmission electron microscope: the axon of DAG neurons in striatum appeared neural sheath disaggregation, the structure of neurofilament and neurotubule were severe disorder and discontinuation, the microtubule disaggregation was observed in axon, the quantity of neurofilament and neurotubule decreased obviously and majority were fragmentation, only a fewer neurofilament and neurotubule were continuous. The mitochondrion was swelling and disaggregation, the mitochondrial cristae was blurry and even disappearance completely. Not only the number of synapse decreased obviously but also the configuration of remained synapse was shrinkage. Conclusions First: the findings suggest that disruption and degeneration of the dendritic arbor and axon is an early indicator of neurodegeneration of dopaminergic neurons in substantia nigra on MPTP-induced PD in C57BL mice. Dying-back neuropathies are characterized by a sequence that progresses from loss of synaptic function to distal axonopathy and eventually to dopaminergic neuron death, dopaminergic neuron death commonly occurs in a sequence of morphological changes that begins with loss of TH-immunolabeled dendritic processes and axon. Second: There is a spontaneous recovery phenomenon in MPTP-induced PD mice model, especially acute PD model, the recovery of morphous and function in axon and axon terminal may precede the recovery of DAG neuron cell body and function. In other words, MPTP-treated mice have a potential for spontaneous regenerative sprouting in nigrostriatal dopaminergic system, the regenerative sprouting in axon and axon terminal are the premise and fundament for spontaneous recovery in MPTP-induced PD mice model. Third, it is very easy that the spontaneous recovery in MPTP-induced PD mice model to be injury by MPTP. The fast degeneration and necrosis of the regenerative sprouting in axon and axon terminal are first and major pathologic changes in reinjury of spontaneous recovery of MPTP-induced PD mice model. Third: The results that we have developed may prove valuable in investigating the mechanisms of degeneration and recovery of substantia nigra dopaminergic neurons; it is important enlightenment significance for PD in the strategy of prevention, therapeutic avenues and rehabilitation.
目的1、本实验通过建立MPTP诱导的C57BL小鼠PD急性、亚急性及慢性动物模型,探讨轴突变性在中脑黑质多巴胺能神经元变性中所起的作用,以及轴突变性对纹状体多巴胺含量的影响,判断轴突及轴突终末变性与多巴胺能神经元变性之间的相互关系及发生的先后顺序;2、通过建立急性、亚急性及慢性PD动物自发恢复模型,探讨轴突及轴突终末“出芽”再生在PD动物模型恢复中所起的作用,以及轴突及轴突终末“出芽”再生对纹状体DA含量的影响,判断PD动物模型自发恢复时DAG神经元胞体及轴突、轴突终末的主要形态学改变; 3、通过建立急性、亚急性及慢性PD模型自发恢复后再损伤模型,探讨轴突及轴突终末变性在再损伤中所起的作用及其机制。为PD发病机制及恢复机制的研究、PD的预防、治疗和康复提供实验依据。方法与结果第一部分实验(MPTP诱导C57BL小鼠PD模型多巴胺能神经元及轴突的损伤):大龄C57BL小鼠55只(32-34w),按给与MPTP的剂量、间隔时间及持续时间不同随机分为4组:对照组、急性组、亚急性组和慢性组,依据PD小鼠出现症状的严重程度及行为学检测(包括爬杆实验、游泳实验、悬挂实验及提尾倒立实验)结果,确定PD动物模型临床分期(包括临床前期、临床早期、临床中期及临床晚期)。各组中分别于临床前期、临床早期、临床中期及临床晚期各处死三只模型小鼠,一只行中脑黑质致密部及纹状体免疫组化染色(包括TH染色、FJC染色)观察多巴胺能神经元胞体及纹状体神经纤维、轴突终末的变性、坏死情况;一只进行透射电镜检查中脑黑质多巴胺能神经元胞体及其投射到纹状体的轴突及轴突终末、突触的超微结构变化情况,一只用高效液相色谱仪-液质联用法检测纹状体内DA、HVA及DOPAC的含量。结合小鼠出现PD症状的早晚,动态观察、比较黑质致密部多巴胺能神经元胞体、轴突、树突及其投射到纹状体的轴突、轴突终末、突触等结构那一个先发生变性、坏死,变性的程度及先后顺序。结果:各组模型均先后出现了PD的症状,并逐渐加重;随临床分期的逐渐加重,PD模型小鼠黑质TH-ir神经元数目进行性减少,与对照组比较,临床前期、临床早期、临床中期及临床晚期分别下降29.6%、44.5%、66.7%及78.4%;DA及DOPAC、HVA含量也呈逐渐下降趋势,纹状体内DA含量分别下降为56.3%、71.5%、84.1%及91.3%,模型组TH-ir细胞计数结果及纹状体DA含量与正常对照组比较均有统计学差异(P< 0. 01),纹状体内TH-ir神经纤维积分光密度值进行性下降。MPTP小鼠PD模型不但SNc内TH-ir神经元细胞数目明显减少,而且TH-ir细胞的轴突及树突数目减少及损害程度要严重于细胞数目的减少及损害,神经纤维纤细且短,严重者甚至轴突完全消失。模型组中临床前期及临床早期小鼠的残留DAG神经元细胞轴突表现为轴突变细,长度缩短,粗细不均匀呈串珠样改变,并且走行迂曲,有轴浆运输障碍表现。FJC染色阳性细胞仅出现在MPTP小鼠模型黑质致密部,细胞计数结果是急性模型>亚急性模型>慢性模型,JFC阳性细胞仅保留有变性的细胞体,轴突及树突未显示,仅个别细胞出现残存的轴突根部,提示变性细胞的轴突及树突已先于胞体变性、消失,不能被FJC染色。透射电镜检查结果:在临床前期或临床早期阶段,PD模型黑质内DAG神经元超微结构及细胞器形态均正常的情况下,纹状体内DAG神经元轴突已经出现变性的早期表现,如局部膨大,膨大处线粒体肿胀变形,线粒体嵴不清甚至消失,出现空泡化,轴突局部膨大处神经微管及神经微丝结构紊乱,不连续,有微管解聚表现,提示轴突变性在先,而DAG神经元胞体的变性在后。第二部分实验(MPTP诱导C57BL小鼠PD模型多巴胺能神经元及轴突、轴突终末损伤后的自发恢复):低龄C57BL小鼠55只(6-8w)随机分为对照组、急性组、亚急性组和慢性组。PD动物模型建立成功后观察其行为学有无自发恢复现象,并再次进行行为学测试确定恢复时期的临床分期,分别于各期处死3只小鼠模型,行中脑黑质致密部及纹状体免疫组化染色(包括TH染色、FJC染色)观察多巴胺能神经元胞体及纹状体神经纤维、轴突终末的变性、坏死情况及再生情况; 3只测纹状体DA、HVA及DOPAC的含量; 3只进行透射电镜检查中脑黑质多巴胺能神经元胞体及其投射到纹状体的轴突、轴突终末、突触的超微结构变化情况,并分别与第一部分实验中临床晚期、临床中期、临床早期及临床前期的电镜结果比较,观察黑质的多巴胺能神经元胞体、胞内细胞器及其投射到纹状体的轴突、轴突终末及突触的变化情况,恢复再生情况。结合模型小鼠恢复情况,动态观察、比较SNc内DAG神经元细胞数、胞体、轴突、树突、突触及纹状体TH-ir神经纤维积分光密度值变化情况,观察纹状体DA的含量是否随症状的缓解而逐渐升高,并且观察DA含量的升高与SNc内DAG神经元胞体的恢复及投射到纹状体的轴突、轴突终末的再生有无关系。结果:急性模型及慢性模型组中动物PD症状能达到临床晚期的比率较亚急性要高,急性模型几乎均有自发恢复现象(恢复率100%),恢复的程度也明显高于另外两种模型;慢性模型PD症状比较典型,但该型模型一旦建立成功,自发恢复现象不明现,有逐渐加重的趋势。恢复期虽然PD模型临床分期在好转,纹状体内DA含量随临床分期好转逐渐升高,与对照组比较,从临床晚期到临床前期,恢复率分别为10.7%、35.1%、44.8%和67.5%。但TH-ir细胞数却仍然在逐渐减少,与对照组比较,临床晚期减少76.3%,恢复到临床中期、早期及前期时分别减少78.4%、82.4%和85.2%。PD小鼠模型恢复期纹状体区TH-ir神经纤维积分光密度值随PD模型临床分期的恢复呈逐渐增高趋势(最低是临床晚期的小鼠)。MPTP小鼠PD模型从临床晚期自发恢复到临床前期时TH染色,虽然残存细胞总数少于临床晚期,但胞体增大,饱满,细胞形态恢复到正常的梭形或多角形,胞浆丰富,核仁居中,胞体轴突及树突粗大,数量多,TH-ir纤维密集粗大成束,走行流畅规律,说明胞体及轴突形态明显改善,可能是残存的轴突及轴突终末通过侧支“出芽”方式再生,恢复了正常的直径。小鼠PD模型自发恢复到临床早期及临床前期的FJC染色结果: SNc内仅有少量的FJC阳性细胞,胞体皱缩,体积缩小,形态不规则,排列紊乱,与刚变性死亡的细胞形态基本接近正常细胞形态不同。电镜结果:DAG神经元胞体形态大小恢复,细胞质中细胞器较丰富,可见丰富的粗面内质网、游离核糖体及数量较多的线粒体,脂褐素较少,有自噬泡出现,细胞核大呈卵圆形,核膜清晰完整,皱褶消失;纹状体内突触数量明显增多,且突触的数量恢复先于胞体结构的恢复,线粒体数量增多,形态及结构完整,线粒体嵴明显;纹状体内轴突肿胀及局部膨大均消失,髓鞘及神经微管、神经微丝排列整齐,连续性好,密集,走行自然,未见断裂及缠结,未见到髓鞘松解断裂现象。恢复期中脑黑质内DAG神经元胞体及轴突的超微结构、纹状体内突触数量恢复情况随临床分期的改善而逐渐好转。第三部分实验(MPTP诱导C57BL小鼠PD模型多巴胺能神经元及轴突损伤自发恢复后再损伤):低龄C57BL小鼠(6-8w)35只随机分对照组、急性组、亚急性组及慢性组,注意观察其行为学方面有无自发恢复现象,并再次进行行为学测试确定恢复时期的临床分期。将从临床晚期逐渐自发恢复到临床早期或临床前期的PD模型小鼠于症状稳定后的第10～15天,再次按30mg/kg腹腔注射MPTP一次,建立恢复后再损伤PD模型。观察小鼠的行为学表现,于注射MPTP后第二天开始处死小鼠,一部分行中脑黑质致密部及纹状体免疫组化染色(包括TH染色、FJC染色)观察多巴胺能神经元胞体及纹状体神经纤维、轴突、轴突终末的变性、坏死情况;另外一部分检测纹状体内DA、HVA及DOPAC的含量;另取一只进行透射电镜检查中脑黑质多巴胺能神经元胞体及其投射到纹状体的轴突、轴突终末、突触的超微结构变化情况,并分别与第一部分实验中临床晚期、临床中期、临床早期、临床前期及第二部分实验中恢复期模型小鼠的电镜结果比较,观察黑质的多巴胺能神经元胞体、胞内细胞器及其投射到纹状体的轴突、轴突终末及突触的变化情况,恢复再生情况及再损伤后的改变情况。结果:共有14只小鼠症状发展到临床晚期,其中有8只出现自发恢复趋势,分别恢复至临床前期至临床中期。再次腹腔注射MPTP一次,注射后小鼠的急性毒性反应较第一次注射时明显减轻,但于注射10h后,迅速出现PD晚期的症状,于注射MPTP后3天开始死亡。纹状体内DA、DOPAC、HVA的含量均急剧减少,与对照组比较,DA含量减少94.2%,DOPAC及HVA各下降了85.1%和76.8%;纹状体区TH-ir神经纤维积分光密度值与对照组比较极低;TH染色发现黑质致密部TH阳性细胞极少,仅6.5±0.6,较对照组减少91.9%;轴突及树突不明显,偶可见轴突根部残留较短的突起,TH-ir纤维稀疏,走行紊乱; FJC染色示SNc内仅有少量的阳性细胞,胞体形态仍接近正常细胞的梭形或不规则多角形,提示是刚发生变性坏死的DAG神经元细胞,胞体的基本形态尚存,但未见细胞轴突及树突显影。电镜结果:MPTP小鼠PD模型自发恢复后再损伤时纹状体内DAG神经元细胞的轴突髓鞘崩解,轴突内神经微管及神经微丝结构严重紊乱,数量明显减少,多数已断裂,仅有少量的神经微管连续,有解聚、崩解、断裂现象,变性程度严重;轴突内线粒体变性,线粒体嵴消失,出现崩解现象;纹状体内突触数量明显减少,残存突触结构形态缩小,突触面宽度变窄。结论:1、MPTP所致的C57BL小鼠PD模型轴突变性、树突消失或断裂是黑质多巴胺能神经元变性的早期标志, DAG细胞以“枝叶枯萎”的细胞死亡方式调亡,即首先突触功能丧失,再到远端轴突病理改变,最后导致细胞死亡;2、MPTP诱导的C57BL小鼠PD模型行为学有自发恢复现象,尤其是急性模型,神经元轴突和轴突终末形态及功能恢复可能早于DAG神经元胞体的恢复及DA合成功能的恢复,即轴突形态及功能恢复可能是PD模型自发恢复的前提和基础; 3、MPTP诱导的C57BL小鼠PD模型行为学自发恢复后易被MPTP再损伤,新生轴突及轴突终末的快速变性坏死是自发恢复后再损伤模型的首先和主要病理改变。提示轴突及轴突终末变性与再生在PD的发病及进程中起着十分重要的作用,对研究多巴胺能神经元变性及恢复机制、对PD的预防、治疗、康复策略有重要的启示意义。
Objective The aims were triple. First, we investigated whether the early loss of axon and dendrites of substantia nigra dopaminergic neurons was specific for MPTP-induced Parkinson’s diseas in C57BL mice model (including acute model, subacute model and chronic model), to explore the role of axonal degeneration in the degeneration of substantia nigra dopaminergic neurons as well as the association with the level of dopamine in striatum and conclude the mutual relationship of axonal degeneration and dopaminergic neuron degeneration. As a secondary aim, we investigated whether the phenomenon of spontaneous recovery of MPTP-induced PD mice model (including acute model, subacute model and chronic model) may be relevant to the regenerative sprouting of remained axon. To explore the role of axonal regenerative sprouting in nigrostriatal dopaminergic system of spontaneous recovery of MPTP-induced PD mice model. As well as axonal regenerative sprouting influence for the level of dopamine in striatum and conclude the major changes of morphology in the striatum and substantia nigra of midbrain of spontaneous recovery of MPTP-induced PD mice model. Third, we first raise reinjury of spontaneous recovery of MPTP-induced PD mice model (including acute model, subacute model and chronic model) and probe the role and mechanism of axonal degeneration in reinjury of spontaneous recovery of MPTP-induced PD mice model (including acute model, subacute model and chronic model). We hope provide a new evidence of theory for PD in the pathogenesy, recovery mechanism, prevention, therapeutic avenues and rehabilitation. Methods and results First experiment ( The degeneration of dopaminergic neuron and axon on MPTP-induced Parkinson’s disease in C57BL mice) : The PD models were formed with intraperitoneal injections of MPTP in old C57BL mice, according to dosage of MPTP, intermission time and persistence time, fifty-five old mice random were divided into control group (saline group), acute group, subacute group and chronic group. Then according to severe degree of PD symptoms and results of behavioral test (for example, Pole test, Swim-test, Traction test and Elevated body swing test) to determine clinical stage of animal model (for example, preclinical phase, clinical early phase, clinical intermediate stage and clinical advanced stage. Three mice models were executed and perfused in every group at preclinical phase, clinical early phase, clinical intermediate stage and clinical advanced stage, respectively. One mouse model’s substantia nigra of midbrain and striatum was treated by Tyrosine hydroxylase (TH)-immunocytochemistry and FJC dyeing, to survey the dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. Another one mouse model’s substantia nigra of midbrain and striatum was treated by electron microscope, to survey the ultramicrostructure of the dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. Third model’s DA, DOPAC and HVA contents in the striatum were measured by High performance liquid chromato-graphy and electrochemical detection. We observed the symptoms of PD mice models and recorded the time that symptoms occurrenced sooner and later, such as tremor, rigidity and bradykinesia, then comparison with the morphological changes of DAG neuron body, axon, dendrite, axon terminal and synapse, at last conclude which one first take place degeneration or necrosis. First experiment results: All group models showed a series of motor functional impairment resembling symptoms of PD and the symptoms become more and more serious. The number of TH-ir neurons gradual decreased (29.6% at preclinical phase, 44.5% at clinical early phase, 66.7% at clinical intermediate stage and 78.4% at clinical advanced stage, respectively) compared to age-matched saline-treated animals. As well as the level of dopamine in striatal also gradual fall-off (56.3% at preclinical phae, 71.5% at clinical early phase, 84.1% at clinical intermediate stage and 91.3% at clinical advanced stage, respectively) in comparison with age-matched saline-treated animals. there are significant difference (P< 0.01). The striatal TH-ir fiber optical density value gradually decreased significantly in comparison with age-matched saline-treated animals. Not only the number and striatal dopamine concentration of TH-ir neurons in SNc obviously decreased by a slow, progressive procedure, but also the number of axons and dendrites declines, and the descending degree of the latter are more severe than the former. The axon of remained DAG neurons was thin and short; crudeness or fineness was inequable and showed a string-of-beads or courser circuity, has an appearance of axoplasmic transport disturbance, even the axon has disappeared completely in some remained DAG neurons. Although left the cell bodies intact but caused a striking fragmentation and apparent degeneration of the dendrites. FJC-ir cell ( namely dopaminergic neurodegenerative neuron) only were discovered in SNc of MPTP-induced PD mice models, the number of FJC-ir cell in the acute model exceed the subacute model and the subacute model exceed chronic model. Although FJC-ir cell remained intact cell bodies, but the axon and dendrites were not immunolabeled or very severe damage, only fewer neurons exhibited relic axonal root. These results indicate that early loss of anox and dendrites is a characteristic morphological feature in the suite of events leading to dopaminergic neurons death. Results of transmission electron microscope: under the circumstances of shape of ultramicrostructure and cellular organ in substantia nigra DAG neurons were normal, such as the cellular nucleus was large and orbicular-ovate, the nuclear membrane was clear and integrity, the lipofuscin scattered in the cytoplasm, there were a lot of rough endoplasmic reticulum, free ribosome, Golgi’s body and mitochondria, the axon of DAG neurons in striatum already have appeared an early appearances of degeneration, for example local intumescentia, the mitochondria was swell in intumescentia, the mitochondrial cristae was blurry and even disappearance completely, the vacuolization was found in mitochondria, the structure of neurofilament and neurotubule were disorder and discontinuation in local intumescentia, the microtubule disaggregation was observed in axon. It indicated that the axonal degeneration was earlier than cell body degeneration. Second experiment (The regeneration of dopaminergic neuron and axon on MPTP-induced Parkinson’s disease in C57BL mice): Fifty-five young mice random were divided into control group (saline group), acute group, subacute group and chronic group.we observed the MPTP-induced PD mice model if have a phenomenon spontaneous recovery and again determined the clinical stage during the recovery period by behavioral test. Three mice models were executed and perfused at preclinical phase, clinical early phase, clinical intermediate stage and clinical advanced stage, respectively. Among three PD mice model’s substantia nigra of midbrain and striatum was treated by Tyrosine hydroxylase (TH)-immunocytochemistry and FJC dyeing, to survey the degeneration, necrosis and regeneration of dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. DA, DOPAC and HVA contents in the stiatum were measured in other three PD mice models. the last three PD mice model’s substantia nigra of midbrain and striatum was treated by electron microscope, to survey the ultramicrostructure of the dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal, and in comparison with first part experiment, at last conclude a conclusion if MPTP-induced PD mice model have a phenomenon of spontaneous recovery, whether or not the striatal TH-ir fibers optical density value and DA contents have a gradually increased tendency with the improvement of PD animal model’symptoms. As well as the recovery of PD animal model with relation to regeneration of axon and the sprouting of dopaminergic axonal terminals. Second experiment results: All group MPTP-induced C57BL young mice have a substantial reduction of striatal dopamine level, the TH-ir fibers optical density value and number of TH-ir cell bodies were also markedly reduced after the toxin treatment. The symptoms of PD were observed following MPTP treatment, especially, acute model and chronic model showed more serious symptoms than subacute model. Thereafter, the symptoms of acute and subacute models showed a spontaneous recovery phenomenon within a few weeks after the toxin treatment. Especially acute PD model, the recovery rate almost gets 100%. However, the chronic PD mice were somewhat different from the acute and subacute PD mice, which showed a typical PD symptoms and become more and more serious, only a fewer models showed a slightly recovery. In the the recovery period, the dopamine content in striatum progressively increased significantly (by 10.7% at clinical advanced stage, by 35.1% at clinical intermediate stage, by 44.8% at clinical early phase and by 67.5% at preclinical phase, respectively) in comparison with age-matched saline-treated animals, from clinical advanced stage to preclinical phase onwards, although the number of TH-ir neurons remained fall off , from clinical advanced stage to preclinical phase, the number of TH-ir neurons declined by 76.3%, 78.4%, 82.4% and 85.2% in comparison with age-matched saline-treated animals, respectively. Tyrosine hydroxylase (TH)-immunocytochemistry was employed for the manifestation of the striatal TH-ir fibers and confocal microscopy was used to determine the optical density value of TH-ir fibers in the striatum. During the recovery period, the striatal TH-ir fiber optical density value of MPTP-induced PD model progressively increased from clinical advanced stage to preclinical phase. TH- immunohistochemical analysis showed that although the number of remained TH-ir neurons in stage of recovery was less than clinical advanced stage, but the cell body of TH-ir neurons is large and full, kytoplasm abundant and nucleolus in centre, the morphous of neurons have recovered normal fusiform shape or polygon. The anox and dendritic processes were frequently apparent and intensive and fasciculation in the remained dopaminergic neurons in substantia nigra. These results indicate that MPTP-treated mice have a potential for spontaneous regenerative sprouting in nigrostriatal dopaminergic system. There are a few FJC-ir cell, the FJC-ir cell bodies appeared to shrink, lose cytoplasmic material, and become detached from neighboring cells, the morphous became irregular and disorder, the volume of degenerating neurons became smaller and concentrationer. It is different from normal morphous of cell。Results of transmission electron microscope: The shape of ultramicrostructure and cellular organ in substantia nigra DAG neurons were normal, such as the cellular nucleus was large and orbicular-ovate, the nuclear membrane was clear and integrity, the reductus was disappearance, the lipofuscin was few in the cytoplasm, there were a lot of rough endoplasmic reticulum, free ribosome, Golgi’s body and mitochondria.The number of synapsis increased obviously in the striatum, and the recovery of synaptic quantity preceded the recovery of cell body, The number of mitochondria increased obviously in synapse, it’s shape and structure were integrity. The axonal swell and local intumescentia have already disappeared completely, the neural sheath, neurotubule and neurofilament lined up in order and intensive, the continuity was fine and natural, the neural sheath fragmentation and solution wasn’t observed in the striatum. During the recovery period, the DAG neurons, ultramicrostructure of axon and the synaptic quantity in striatum were more and more advancement with the improvement of symptoms of PD models. Third experiment (The reinjury of the regeneration of dopaminergic neuron and axon on MPTP-induced Parkinson’s disease in C57BL mice): Thirty-five young mice random were divided into control group (saline group), acute group, subacute group and chronic group. We careful observed the MPTP-induced PD mice model if have a phenomenon spontaneous recovery and again determined the clinical stage during the recovery period by behavioral test. Then chose MPTP-induced PD mice model which recovery from clinical advanced stage to preclinical phase and again raised from ten day to fifteen day after stabilization of symptoms. The reinjury PD model was raised by injecting MPTP with a dose 30 mg/kg again. The reinjury PD model were killed on second day. Some reinjury PD mice model’s substantia nigra of midbrain and striatum was treated by Tyrosine hydroxylase (TH)-immunocytochemistry and FJC dyeing, to survey the degeneration, necrosis and regeneration of dopaminergic neuron, axon, striatal TH-ir fibers and axon terminal. DA, DOPAC and HVA contents in the stiatum were measured in other reinjury PD mice models, one reinjury PD mouse model’s substantia nigra of midbrain and striatum was treated by electron microscope, to survey the ultramicrostructure and restorative regeneration of the dopaminergic neurons, axon, distal dendrites, striatal TH-ir fibers, axon terminals, cell organ and synapse and in comparison with first part and second experiment results. Third experiment results: fourteen PD mice models advanced to clinical advanced stage, among the total eight PD mice models showed a spontaneous recovery tendency, the degree of recovery from clinical intermediate stage to preclinical phase. When we again injected MPTP (30mg/kg), the acute toxic reaction was light than first injection, but the reinjury PD mice models fast appearanced a symptoms of clinical advanced stage after injecting MPTP ten hours. Some PD models gradually died. We have observed a robust depletion of striatal DA and its metabolite, DOPAC and HVA. the dopamine content in striatum depleted by 94.2%, DOPAC decreased by 85.1% and HVA declined by 76.8% in comparison with age-matched saline-treated animals, the striatal TH-ir fibers optical density value was extreme low in comparison with age-matched saline-treated animals, the number of TH-ir neurons was scanty in SNc, only about 6.5±0.6, The number of dopaminergic neurons in the substantia nigra were declined about 91.9%in comparison with age-matched saline-treated animals. The axons and dendrites of remained DAG neurons were not apparent, occasionally can find a short axonal root in residual processes. The TH-ir fibers were sparseness and courser disorder. FJC-dyeing found only a few FJC-ir cells in SNc, but the cell body of FJC-ir neurons is approximately normocellular figure, such as kytoplasm abundant, fusiform shape or polygon. It indicated that these cells died in a short time. Results of transmission electron microscope: the axon of DAG neurons in striatum appeared neural sheath disaggregation, the structure of neurofilament and neurotubule were severe disorder and discontinuation, the microtubule disaggregation was observed in axon, the quantity of neurofilament and neurotubule decreased obviously and majority were fragmentation, only a fewer neurofilament and neurotubule were continuous. The mitochondrion was swelling and disaggregation, the mitochondrial cristae was blurry and even disappearance completely. Not only the number of synapse decreased obviously but also the configuration of remained synapse was shrinkage. Conclusions First: the findings suggest that disruption and degeneration of the dendritic arbor and axon is an early indicator of neurodegeneration of dopaminergic neurons in substantia nigra on MPTP-induced PD in C57BL mice. Dying-back neuropathies are characterized by a sequence that progresses from loss of synaptic function to distal axonopathy and eventually to dopaminergic neuron death, dopaminergic neuron death commonly occurs in a sequence of morphological changes that begins with loss of TH-immunolabeled dendritic processes and axon. Second: There is a spontaneous recovery phenomenon in MPTP-induced PD mice model, especially acute PD model, the recovery of morphous and function in axon and axon terminal may precede the recovery of DAG neuron cell body and function. In other words, MPTP-treated mice have a potential for spontaneous regenerative sprouting in nigrostriatal dopaminergic system, the regenerative sprouting in axon and axon terminal are the premise and fundament for spontaneous recovery in MPTP-induced PD mice model. Third, it is very easy that the spontaneous recovery in MPTP-induced PD mice model to be injury by MPTP. The fast degeneration and necrosis of the regenerative sprouting in axon and axon terminal are first and major pathologic changes in reinjury of spontaneous recovery of MPTP-induced PD mice model. Third: The results that we have developed may prove valuable in investigating the mechanisms of degeneration and recovery of substantia nigra dopaminergic neurons; it is important enlightenment significance for PD in the strategy of prevention, therapeutic avenues and rehabilitation.
引文
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