MicroRNAs与帕金森病关系的研究进展

帕金森病(Parkion's disease,PD)作为一种复杂的神经系统退行性疾病,已经成为严重影响中老年人健康及生活质量的重要疾病之一。病理变化为中枢神经系统黑质及纹状体通路的多巴胺(Dopamine,DA)能神经元发生退行性变性以及纹状体DA含量的减少,导致纹状体内DA和乙酰胆碱平衡失调而发病。其发病机制尚不明确,但普遍认为可能是遗传易感性、环境毒素几种因素共同作用的结果,而导致黑质DA能神经元变性凋亡则与氧化应激、蛋白酶体功能异常、自我吞噬、蛋白质合成减少、转录信号改变等因素关系密切。近年来,人们从各个相关领域对其进行深入研究,其发病机制正逐步被人们所破解。小NRA(miRNA,mircoRNA)是一类非编码miRNA,通过与mRNA靶基因互补配对调控转录后水平的基因表达。miRNA对神经元细胞中的信号调控具有重要作用,目前关于miRNA与PD之间的关系越来越受到重视。本综述通过对miRNA与PD关系的探讨,为研究PD的致病机制提供新的线索,从而为PD患者治疗提供一个新的视角。     

胶质细胞在帕金森病神经元铁聚积及退变中的作用

越来越多的证据表明胶质细胞在中枢神经系统发育、神经元的存活、神经修复与再生、突触传递及免疫炎症等方面均具有重要的功能。近年来,胶质细胞在帕金森病(Parkinson’s disease,PD)中的作用受到越来越多的关注。大量的研究证实,中脑黑质(substantia nigra,SN)部位铁聚积参与了PD多巴胺(dopamine,DA)神经元的死亡。目前PD铁沉积的研究主要集中在DA神经元,但实际上脑内胶质细胞在中枢神经系统铁稳态调节中发挥着重要的作用。因此,本文综述了胶质细胞铁代谢及其参与DA神经元铁聚积及死亡的作用机制,为揭示PD患者SN部位铁聚积的机制以及发现潜在的治疗靶点提供理论依据。     

多巴胺转运体功能及其与神经精神疾病的相关研究

中枢神经系统(central nervous system,CNS)环路是注意力、奖赏应答和动机等精神活动的基础,而神经递质多巴胺(dopamine,DA)在这一环路中起关键作用。多巴胺转运体(dopamine transport,DAT)位于突触前体,重新摄取DA,维持突触多巴胺有效性和多巴胺能神经元的协调性。多巴胺转运体功能异常会导致脑内多巴胺平衡失调,从而引起精神兴奋剂依赖、帕金森病(Parkinson disease,PD)、精神分裂症及注意力缺陷多动障碍(attention-deficit hyperactivity disorder,ADHD)等多种神经精神疾病。本文从DAT的结构与功能及其在多巴胺信号调节中的分子机制,DAT与精神兴奋剂依赖等疾病关系的相关研究进行了论述。     

多巴胺D3受体(D3R)的神经科学新进展

多巴胺(DA)是脑内一种重要的神经递质,通过不同DA受体亚型调控运动功能、认知活动和药物成瘾等生理、病理过程。多巴胺D3受体(D3R)属于D2样受体,但其功能长期不明。近年来,人们对它在神经科学中的意义有了新的认识。首先,D3R的信号通路独特,它被激活后显示细胞增殖效应,但cAMP信号传导途径不明显。其次,D3R基因敲除小鼠研究提示,正常生理状态下D3R仅表现辅助功能：在特定病理条件下,D3R显示出重要的“平衡缓冲作用”,在精神分裂症、帕金森病(PD)治疗中运动障碍副作用LID的发生和毒品复吸等病理过程扮演了重要角色。因此,D3R是一个重要的药物靶标。D3R拮抗剂在精神分裂症治疗中显示了临床前景,D3R激动剂则对PD治疗和毒品复吸防治展示了应用价值。     

间充质干细胞移植治疗帕金森病的作用机制研究进展

帕金森病(Parkinson’s Disease,PD)的主要病理改变是黑质多巴胺能神经元进行性变性致纹状体多巴胺递质浓度显著降低,从而出现运动障碍。目前,药物和外科手术治疗可一定程度改善早期PD的部分临床症状,但并不能阻止或逆转多巴胺能神经元变性。近些年,间充质干细胞(Mesenchymal Stem Cells,MSCs)移植作为治疗PD的最前沿方法,其疗效备受瞩目。本文就MSCs移植促进PD神经功能恢复的可能作用机制作一综述。     

丘脑底核-深部脑刺激术术后淡漠的研究进展

帕金森病(Parkinson's disease,PD)是一种由于中脑黑质以及其他核团结构的多巴胺能神经元变性所致的以进行性运动功能障碍为主要表现的疾病。近年来,双侧高频刺激的丘脑底核-深部脑刺激术(STN-DBS)治疗PD效果确切,疗效较好,但其出现了术后淡漠等类似副作用,严重影响了PD治疗效果和患者的生活质量,引起了临床医生的高度重视。本文对STN-DBS术后淡漠发病情况、表现及治疗进行综述,为临床诊治提供思路。     

帕金森病氧化应激机制及抗氧化药物治疗进展

帕金森病(PD)是一种仅次于阿尔兹海默病的第二大神经系统变性疾病,随着社会人口老龄化,PD发病率逐年增高,在65岁以上的老年人,患病率高达1%。PD主要临床表现为静止性震颤、肌强直、运动迟缓、姿势步态异常。目前病因仍未明确,疾病发生与很多因素相关,其主要病理特征为黑质多巴胺能神经元变性缺失。研究发现线粒体功能障碍、钙超载、铁离子的堆积、免疫炎症等均与氧化应激有关,能造成氧化性损伤,促进多巴胺能神经元凋亡,氧化应激在促进PD疾病发展中起到重要作用,因而越来越备受关注,抗氧化治疗在某种程度上为PD的治疗指出新的方向。本文就氧化应激引起DA神经元变性缺失的机制及抗氧化药物的治疗进展进行综述。     

BDNF基因工程细胞对帕金森大鼠纹状体多巴胺及其代谢物影响的研究

目的:观察经侧脑室移植pIRESneo-EGFP-BDNF修饰骨髓间充质干细胞(MSCs)对帕金森病(PD)大鼠纹状体多巴胺(DA)及代谢产物的影响。方法:采用电穿孔法将pIRESneo-EGFP-BDNF转染至骨髓MSCs;制备PD大鼠模型,随机分为Sham组,PD组,MSCs组,脑源性神经生长因子(BDNF)组,经侧脑室移植MSCs或pIRESneo-EGFP-BDNF修饰骨髓MSCs,术后2周,4周,8周,腹腔注射阿朴吗啡(APO)诱导PD大鼠旋转行为;应用高效液相色谱测定各组大鼠纹状体内多巴胺(DA)、高香草酸(HVA)及二羟苯乙酸(DOPAC)。结果:移植术后2周,4周,8周BDNF组、MSCs组大鼠与PD组比较旋转次数明显减少(P<0.05),以BDNF组改善更为明显。移植细胞干预PD模型8周后BDNF组、MSCs组大鼠纹状体DA、HVA、DOPAC较PD组明显提高(P<0.01),以BDNF组更为显著。结论:经侧脑室移植pIRESneo-EGFP-BDNF修饰的骨髓MSCs干预PD大鼠模型,显著降低PD大鼠纹状体内DA代谢率,提高DA水平,改善PD大鼠的行为能力。     

人参总皂苷在神经干细胞移植治疗帕金森模型小鼠中的体内作用

目的：观察预先给小鼠体内注射人参总皂苷（TSPG）后,对帕金森病（PD）模型的建立以及神经干细胞（NSCs）移植的影响。方法：实验分5组。1～4组常规采用1-甲基4苯基-1,2,3,6-四羟吡啶（MPTP）建立PD小鼠模型;第5组建模前体内注射TSPG,干预PD模型的建立。建模前后用行为学指标以及震颤麻痹评分标准对模型进行评判。然后取第9周人胚胎大脑皮层NSCs,经TSPG预处理后植入上述5组PD小鼠纹状体内。移植60d后脑切片,做酪氨酸羟化酶（TH）免疫组化染色检测NSCs的分化状况。结果：体内预先注射TSPG能有效降低由MVFP引起的神经细胞损伤;在神经干细胞移植后,与其余4组相比,其震颤麻痹、自发活动、记忆功能的改善更为明显,脑切片中的多巴胺（DA）能神经元数量以及与相邻神经元建立的联系更为丰富。结论：TSPG的体内用药,可以更好的降低神经系统损害。并在NSCs移植治疗PD中发挥更好的作用。     

帕金森氏病的病因及表现和治疗

帕金森氏病（Parkinsondiseas。PD）又称震颤麻痹,是发生于中年以上的中枢神经系统变性疾病,以震颤、肌强直反运动减少为主要临床特征入8厂年由英国医生帕金森门OO。。Parkinson）苗先报道。脑炎、动脉硬化、颅脑损伤、一氧化碳、锰、汞及某些抗精神病药物等中毒也可产生与原发性帕金森氏病类似的症状,这种继发者称为帕金森氏综合症。本文重点谈谈帕金森氏病的病因、表现和治疗。亚病因和发病机制到目前为止,Plj的确切病因尚未完全明确。患者中脑黑质多巴胺（DA偷神经元变性坏死、酪氨酸羟化酶（＊N）减少成活性降低,使脑纹状体多…     

抗氧化剂依达拉奉联合葛根素用于帕金森病治疗的临床观察

目的:观察西药抗氧化剂依达拉奉联合中药葛根素在帕金森病治疗中的效果及安全评价。方法:选取2011年8月-2013年12月哈尔滨医科大学附属第四医院神经内科收治的帕金森病人80例,随机均分为实验组和对照组。实验组给予口服美多巴,同时静滴依达拉奉和葛根素,对照组仅予口服美多巴治疗,疗程2周,治疗前后比较UPDRS评分、不良反应,观察血清氧化酶学指标的变化。结果:治疗后,实验组的四项UPDRS评分改善均显著优于对照组,且实验组不良反应亦显著低于对照组;两组患者的血清氧化酶学指标检测与治疗前比有明显改善,差异均具有统计学意义(P0.05)。结论:在口服美多巴治疗基础上,联合应用依达拉奉和葛根素,对帕金森病的治疗显示出更好的效果,并有利于减轻药物的不良反应,可能跟调控抗氧化酶有关。     

Stem cell potential in Parkinson's disease and molecular factors for the generation of dopamine neurons

Parkinson's disease (PD) involves the loss of dopamine (DA) neurons, making it the most expected neurodegenerative disease to be treated by cell replacement therapy. Stem cells are a promising source for cell replacement therapy due to their ability to self-renew and their pluripotency/multipotency that allows them to generate various types of cells. However, it is challenging to derive midbrain DA neurons from stem cells. Thus, in this review, I will discuss the molecular factors that are known to play critical roles in the generation and survival of DA neurons. The developmental process of DA neurons and functions of extrinsic soluble factors and homeodomain proteins, forkhead box proteins, proneural genes, Nurr1 and genes involved in epigenetic control are discussed. In addition, different types of stem cells that have potential for future cell replacement therapy are reviewed.     

幽门螺杆菌根除治疗对帕金森病患者运动症状的影响

目的:探讨幽门螺杆菌(HP)根除治疗对帕金森病(PD)患者运动症状的影响及其安全性,为临床治疗提供参考。方法:选取2013年1月-2015年10月医院收治的PD患者120例,根据尿素呼吸试验(UBT)检测结果,将PD患者分为HP组(n=32)和非HP组(n=88),两组均进行抗PD的常规治疗,HP组在此基础上采用HP根除治疗(奥美拉唑+克拉霉素+阿莫西林),采用帕金森病评定量表(UPDRS)评估两组患者治疗前后的运动症状,并对治疗过程中的不良反应进行统计分析。结果:120例PD患者中,HP感染32例占26.67%,经HP根除治疗后,HP检测阴性者26人,成功根除率81.25%。组间比较,治疗前两组UPDRS Ⅳ评分有统计学差异(P0.05),而UPDRS Ⅲ评分、Hoehn-Yahr分级、"开"期和"关"期时间无统计学差异(P0.05);治疗后两组"开"期和"关"期时间存在统计学差异(P0.05),而UPDRS Ⅲ评分、UPDRS Ⅳ评分、Hoehn-Yahr分级无统计学差异(P0.05)。组内比较,治疗后,HP组UPDRS Ⅲ评分和UPDRS Ⅳ评分均较治疗前下降,差异有统计学意义(P0.05),且"开"期时间明显延长,"关"期时间明显缩短,差异均有统计学意义(P0.05),而非HP组治疗前后上述各项指标比较,差异均无统计学意义(P0.05)。HP根除组不良反应发生率与非HP组相比,差异无统计学意义(P0.05)。结论:HP感染与PD的发生有关,HP根除治疗能显著改善PD患者的运动症状,安全有效,值得临床推广使用。     

Levodopa-induced plasticity: a double-edged sword in Parkinson's disease?

The long-term replacement therapy with the dopamine (DA) precursor 3,4-dihydroxy-l-phenylalanine (L-DOPA) is a milestone in the treatment of Parkinson''s disease (PD). Although this drug precursor can be metabolized into the active neurotransmitter DA throughout the brain, its therapeutic benefit is due to restoring extracellular DA levels within the dorsal striatum, which lacks endogenous DA as a consequence of the neurodegenerative process induced by the disease. In the early phases of PD, L-DOPA treatment is able to restore both long-term depression (LTD) and long-term potentiation (LTP), two major forms of corticostriatal synaptic plasticity that are altered by dopaminergic denervation. However, unlike physiological DA transmission, this therapeutic approach in the advanced phase of the disease leads to abnormal peaks of DA, non-synaptically released, which are supposed to trigger behavioural sensitization, namely L-DOPA-induced dyskinesia. This condition is characterized by a loss of synaptic depotentiation, an inability to reverse previously induced LTP. In the advanced stages of PD, L-DOPA can also induce non-motor fluctuations with cognitive dysfunction and neuropsychiatric symptoms such as compulsive behaviours and impulse control disorders. Although the mechanisms underlying the role of L-DOPA in both motor and behavioural symptoms are still incompletely understood, recent data from electrophysiological and imaging studies have increased our understanding of the function of the brain areas involved and of the mechanisms implicated in both therapeutic and adverse actions of L-DOPA in PD patients.     

Neurobehavioral mechanisms of temporal processing deficits in Parkinson's disease

Background

Parkinson''s disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.

Methodology/Findings

The present study addressed these issues by testing controls and PD volunteers ‘on’ and ‘off’ DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.

Conclusions/Significance

Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity.     

止颤汤联合重复经颅磁刺激治疗帕金森病合并睡眠障碍、抑郁的临床疗效观察

摘要 目的：评价止颤汤联合重复经颅磁刺激（rTMS）治疗帕金森（PD）合并睡眠障碍、抑郁的临床疗效。方法：选入我院2022年9月~2023年1月收治的PD合并睡眠障碍、抑郁患者80例，随机分为对照组和观察组，各40例。对照组予以常规西药+rTMS治疗，观察组在对照组基础上加服中药止颤汤。评价两组的临床疗效、睡眠及抑郁状况等，并进行统计比较。结果：两组治疗后中医证候积分较治疗前下降（P＜0.05），而观察组下降幅度显著高于对照组（P＜0.05）；两组总有效率无明显差异（P＞0.05），但观察组愈显率较对照组高（P＜0.05）；与治疗前比较，两组治疗后UPDRS-Ⅰ、UPDRS-Ⅱ、UPDRS-Ⅲ，NMSE和HAMD量表得分明显下降，PDSS得分明显上升（P＜0.05），而观察组下降幅度更大（P＜0.05）；两组不良反应发生率无差异（P＞0.05）。结论：止颤汤联合rTMS治疗PD合并睡眠障碍、抑郁疗效肯定，可有效改善患者的临床症状，提高睡眠质量，缓解抑郁状态，且安全性良好。     

Preventive role of PD‐1 on MPTP‐induced dopamine depletion in mice

Many current studies of Parkinson's disease (PD) suggest that inflammation is involved in the neurodegenerative process. PD‐1, a traditional Korean medicine, used to treat various brain diseases in Korea. This study was designed to investigate the effect of PD‐1 extract in the Parkinson's model of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) lesioned mice. The MPTP administration caused the dopamine neuron loss in the striatum and substantia nigra pars compacta (SNpc), which was demonstrated by a depletion of tyrosine hydroxylase (TH). In addition, a reduction of bcl‐2 expression with elevation of bax expression, caspase‐3 activation, and release of cytochrome c into cytosol in dopaminergic neurons of SNpc were noted. Oral administration of PD‐1 extract (50 and 100 mg kg^?1) attenuated the MPTP‐induced depletion of TH proteins in the striatum and SNpc and prevented the apoptotic effects. These results indicate that PD‐1 extract is able to protect dopaminergic neurons from MPTP‐induced neuronal death, with important implications for the treatment of PD. Copyright © 2010 John Wiley & Sons, Ltd.     

Aging Reveals a Role for Nigral Tyrosine Hydroxylase ser31 Phosphorylation in Locomotor Activity Generation

Background

Tyrosine hydroxylase (TH) regulates dopamine (DA) bioavailability. Its product, L-DOPA, is an established treatment for Parkinson''s disease (PD), suggesting that TH regulation influences locomotion. Site-specific phosphorylation of TH at ser31 and ser40 regulates activity. No direct evidence shows that ser40 phosphorylation is the dominating mechanism of regulating TH activity in vivo, and physiologically-relevant stimuli increase L-DOPA biosynthesis independent of ser40 phosphorylation. Significant loss of locomotor activity occurs in aging as in PD, despite less loss of striatal DA or TH in aging compared to the loss associated with symptomatic PD. However, in the substantia nigra (SN), there is equivalent loss of DA or TH in aging and at the onset of PD symptoms. Growth factors increase locomotor activity in both PD and aging models and increase DA bioavailability and ser31 TH phosphorylation in SN, suggesting that ser31 TH phosphorylation status in the SN, not striatum, regulates DA bioavailability necessary for locomotor activity.

Methodology and Principal Findings

We longitudinally characterized locomotor activity in young and older Brown-Norway Fischer 344 F₁ hybrid rats (18 months apart in age) at two time periods, eight months apart. The aged group served as an intact and pharmacologically-naïve source of deficient locomotor activity. Following locomotor testing, we analyzed DA tissue content, TH protein, and TH phosphorylation in striatum, SN, nucleus accumbens, and VTA. Levels of TH protein combined with ser31 phosphorylation alone reflected inherent differences in DA levels among the four regions. Measures strictly pertaining to locomotor activity initiation significantly correlated to DA content only in the SN. Nigral TH protein and ser31 phosphorylation together significantly correlated to test subject''s maximum movement number, horizontal activity, and duration.

Conclusions/Significance

Together, these results show ser31 TH phosphorylation regulates DA bioavailability in intact neuropil, its status in the SN may regulate locomotor activity generation, and it may represent an accurate target for treating locomotor deficiency. They also show that neurotransmitter regulation in cell body regions can mediate behavioral outcomes and that ser31 TH phosphorylation plays a role in behaviors dependent upon catecholamines, such as dopamine.     

L-DOPA-induced hyperhomocysteinemia in Parkinson's disease: Elephant in the room

BackgroundDopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive.Scope of reviewProlong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease. In concoction with parkinsonian neurotoxins, Hcy exaggerates dopaminergic neurodegeneration, while its intranigral infusion has been demonstrated to decrease the dopamine level as well as causes dopaminergic neurodegeneration. Therefore, it can be propounded that elevated level of Hcy (hyperhomocysteinemia) is one of the underlying causes of L-DOPA-induced side-effects and aggravates the progressive nature of Parkinson's disease, which has been focused here. We have provided a conjectural discussion on the involvement of Hcy in L-DOPA-induced dyskinesia in Parkinson's disease.ConclusionHyperhomocysteinemia as a result of prolonged L-DOPA therapy is the emerging cause of L-DOPA-induced behavioral abnormalities and progressive nature of Parkinson's disease.General significanceThis review highlights that hyperhomocysteinemia could be a putative contributor of the side-effects of chronic L-DOPA therapy because of its neurotoxic potency.