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1.
目前,帕金森病的发病机理存在各种假说,包括氧化应激与清除自由基能力下降、线粒体功能异常、兴奋性氨基酸的毒性作用、神经营养因子的缺乏、神经炎症机制、基因与环境影响因素、一氧化氮毒性作用和凋亡等。本文就帕金森病的氧化应激、环境影响因素、神经炎症机制作一综述。  相似文献   

2.
帕金森病的病因及发病机制十分复杂,由多因素参与,目前认为病因包括年龄、遗传,发病机制包括氧化应激损伤、兴奋性神经毒性、同型半胱氨酸、免疫炎性反应、线粒体功能缺陷及细胞凋亡及自噬作用等方面,本文将从这几个方面展开综述。  相似文献   

3.
铁与帕金森病相关性研究的近况   总被引:4,自引:0,他引:4  
铁代谢紊乱、铁诱导的氧化应激及自由基生成与帕金森病的发病机制有关 ;而铁螯合剂在离体实验及帕金森病动物模型中均被证实能抑制氧化应激、保护多巴胺能神经元。本文就近年来帕金森病时铁代谢的变化、铁在帕金森病中的可能作用机制及铁螯合剂在帕金森病治疗中的应用前景作一综述。  相似文献   

4.
<正>帕金森病(PD)是最常见的神经系统变性疾病之一,具体发病机制比较复杂。有研究提示线粒体损伤、蛋白质错误折叠及聚集、氧化应激、"朊病毒样蛋白感染"及神经炎症等均有可能参与PD的发病和进展~([1-2])。其中,免疫介导的神经炎症被认为可明显加剧病情,是PD发病机制中的关键促进因素~([3])。明确免疫应答在PD进程中的作用并通过调节免疫反应控制神经炎症成为该领域中的研究热点。本文主要就PD  相似文献   

5.
帕金森病发病机制研究进展:α-synuclein与氧化应激   总被引:2,自引:0,他引:2  
帕金森病 (PD)是一种常见的老年神经变性疾病 ,它的发病机制与遗传因素和环境因素共同作用有关 ,但其内在的联系尚不十分清楚。α synuclein可能起到联系基因和环境因素在PD中的发病机制的作用 ,而多巴胺导致的氧化应激则可能是神经变性的共同途径。本文就α synuclein和氧化应激在PD发病机制中作用等方面的研究作一综述  相似文献   

6.
神经变性疾病的致病因素大都涉及到氧化应激,如自由基增多和脂质过氧化物的聚集等.因此许多神经变性疾病可能存在相同的致病机制而导致共同的临床和病理特征,如帕金森病与肌萎缩侧索硬化都可以具有超氧化物歧化酶(SOD)的降低.目前越来越多的实验及临床证据表明,氧化应激机制在神经系统变性疾病中起着重要作用.  相似文献   

7.
<正>既往认为帕金森病(PD)的病因是遗传因素、环境因素、衰老、氧化应激、线粒体功能障碍等多种因素协同作用的结果。近来神经免疫炎症机制在PD中的作用受到普遍关注。许多临床研究[1,2]发现PD患者血清、CSF的炎性细胞因子水平显著增高,炎症活化T淋巴细胞亚型增多,并且B淋巴细胞产生抗体增多。在PD患者正电子发射计算机断层扫描的研究中,应用示踪剂[11C](R)-PK11195标记激活的小胶质细  相似文献   

8.
α-Synuclein和多巴胺是帕金森病病理学中的核心要素.α-Synuclein异常聚集导致细胞内游离多巴胺含量明显升高,加剧氧化应激;而细胞内游离多巴胺反之又促进α-Synuclein单体的异常聚集,并抑制细胞毒性作用较强的α-Synuclein寡聚体/原纤维向无细胞毒性的成熟纤维转化.二者形成恶性循环,在帕金森病发病中发挥重要的作用,进一步探讨二者之间的相互作用机制有可能成为阐明帕金森病发病机制的新线索.  相似文献   

9.
帕金森病是一种常见的神经系统变性疾病,其发病机制至今不甚明了。流行病学调查发现,吸烟与帕金森病发病之间存在负相关,提示烟碱系统可能与PD关系密切。本文首先阐述了烟碱受体不同亚基在中枢神经系统的分布、功能及与黑质纹状体损害的关系。进而论述了烟碱对PD的症状改善作用,及其通过抑制氧化应激、促进DA的释放、诱导神经营养因子表达等机制而发挥的神经保护作用。  相似文献   

10.
中脑黑质多巴胺能神经元变性是帕金森病的主要病理变化,炎症反应和氧化应激与神经元变性有密切的联系。体内外实验应用脂多糖可诱发小胶质细胞激活,使之释放大量的各种细胞毒性因子(包括NO等自由基),触发炎症反应和氧化应激,选择性使中脑多巴胺能神经元变性死亡,降低酪氨酸羟化酶的活性,使多巴胺水平下降,最终致帕金森病样病理改变。在脂多糖所致的一系列病理变化中,干预小胶质细胞激活及细胞毒性因子的释放,有助于阻止帕金森病的进展。  相似文献   

11.
Most acute and chronic neurodegenerative conditions are accompanied by neuroinflammation; yet the exact nature of the inflammatory processes and whether they modify disease progression is not well understood. In this review, we discuss the key epidemiological, clinical, and experimental evidence implicating inflammatory processes in the progressive degeneration of the dopaminergic (DA) nigrostriatal pathway and their potential contribution to the pathophysiology of Parkinson's disease (PD). Given that interplay between genetics and environment are likely to contribute to risk for development of idiopathic PD, recent data showing interactions between products of genes linked to heritable PD that function to protect DA neurons against oxidative or proteolytic stress and inflammation pathways will be discussed. Cellular mechanisms activated or enhanced by inflammatory processes that may contribute to mitochondrial dysfunction, oxidative stress, or apoptosis of dopaminergic (DA) neurons will be reviewed, with special emphasis on tumor necrosis factor (TNF) and interleukin-1-beta (IL-1beta) signaling pathways. Epigenetic factors which have the potential to trigger neuroinflammation, including environmental exposures and age-associated chronic inflammatory conditions, will be discussed as possible 'second-hit' triggers that may affect disease onset or progression of idiopathic PD. If inflammatory processes have an active role in nigrostriatal pathway degeneration, then evidence should exist to indicate that such processes begin in the early stages of disease and that they contribute to neuronal dysfunction and/or hasten neurodegeneration of the nigrostriatal pathway. Therapeutically, if anti-inflammatory interventions can be shown to rescue nigral DA neurons from degeneration and lower PD risk, then timely use of anti-inflammatory therapies should be investigated further in well-designed clinical trials for their ability to prevent or delay the progressive loss of nigral DA neurons in genetically susceptible populations.  相似文献   

12.
Oxidative stress is well documented in Parkinson's disease (PD) and has been attributed to dopamine oxidative metabolism. However, evidence of oxidative stress is found in a variety of neurodegenerative disorders, suggesting that more general factors are responsible or that cytodestructive processes secondarily generate oxyradical products. Increasing evidence points away from dopamine metabolism as an important contributor to PD neurodegeneration. Predictions from the dopamine oxidative stress hypothesis of PD reveal multiple inconsistencies. Although the clinical and therapeutic importance of the nigrostriatal dopaminergic system is undeniable, PD neuropathology is much more widespread.  相似文献   

13.
There is growing recognition that Parkinson's disease (PD) is likely to arise from the combined effects of genetic predisposition as well as largely unidentified environmental factors. The relative contribution of each varies from one individual to another. Even in situations where more than one family member is affected, the predominant influence may be environmental. Although responsible for only a small minority of cases of PD, recently identified genetic mutations have provided tremendous insights into the basis for neurodegeneration and have led to growing recognition of the importance of abnormal protein handling in Parkinson's as well as other neurodegenerative disorders. Abnormal protein handling may increase susceptibility to oxidative stress; conversely, numerous other factors, including oxidative stress and impaired mitochondrial function can lead to impaired protein degradation. A limited number of environmental factors are known to be toxic to the substantia nigra; in contrast, some factors such as caffeine intake and cigarette smoking may protect against the development of PD, although the mechanisms are not established. We review the various genetic and environmental factors thought to be involved in PD, as well as the mechanisms that contribute to selective nigral cell death.  相似文献   

14.
Parkinson’s disease (PD) is caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in the deficiency of DA in the striatum. Thus, symptoms are developed, such as akinesia, rigidity and tremor. The aetiology of neuronal death in PD still remains unclear. Several possible mechanisms of the degeneration of dopaminergic neurons are still elusive. Various mechanisms of neuronal degeneration in PD have been proposed, including formation of free radicals, oxidative stress, mitochondrial dysfunction, excitotoxicity, calcium cytotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental factors, toxic action of nitric oxide, and apoptosis. All these factors interact with each other, inducing a vicious cycle of toxicity causing neuronal dysfunction, atrophy and finally cell death. Considerable evidence suggests that free radicals and oxidative stress may play key roles in the pathogenesis of PD. However, currently, drug therapy cannot completely cure the disease. DA replacement therapy with levodopa (L-Dopa), although still being a gold standard for symptomatic treatment of PD, only alleviates the clinical symptoms. Furthermore, patients usually experience severe side effects several years after the L-Dopa treatment. Until now, no therapy is available to stop or at least slow down the neurodegeneration in patients. Therefore, efforts are made not only to improve the effect of L-Dopa treatment for PD, but also to investigate new drugs with both antiparkinsonian and neuroprotective effects. Here, the advantages and limitations of current and future therapies for PD were dicussed. Current therapies include dopaminergic therapy, DA agonists, MAO-B inhibitor, COMT inhibitors, anticholinergic drugs, surgical procedures such as pallidotomy and more specifically deep brain stimulation of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN), and stem cell transplantation.  相似文献   

15.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a dramatic loss of dopaminergic neurons in the substantia nigra (SN). Among the many pathogenic mechanisms thought to contribute to the demise of these cells, dopamine-dependent oxidative stress has classically taken center stage due to extensive experimental evidence showing that dopamine-derived reactive oxygen species and oxidized dopamine metabolites are toxic to nigral neurons. In recent years, however, the involvement of neuro-inflammatory processes in nigral degeneration has gained increasing attention. Not only have activated microglia and increased levels of inflammatory mediators been detected in the striatum of deceased PD patients, but a large body of animal studies points to a contributory role of inflammation in dopaminergic cell loss. Recently, postmortem examination of human subjects exposed to the parkinsonism-inducing toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), revealed the presence of activated microglia decades after drug exposure, suggesting that even a brief pathogenic insult can induce an ongoing inflammatory response. Perhaps not surprisingly, non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of developing PD. In the past few years, various pathways have come to light that could link dopamine-dependent oxidative stress and microglial activation, finally ascribing a pathogenic trigger to the chronic inflammatory response characteristic of PD.  相似文献   

16.
Abstract

Objectives: Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by motor dysfunctions. Dopaminergic neuron loss, inflammation and oxidative stress responses play key roles in the pathogenisis of PD. Osthole (Ost), a natural coumarin derivative, isolated from various herbs such as Cnidium monnieri (L.), has anti-inflammatory, anti-apoptotic and anti-oxidative stress properties. However, whether it has effects on PD is unknown.

Methods: In this study, mice were subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection to induce PD symptoms, and treated with osthole. Stepping and cylinder tests were performed to determine their motor function. Immunohistochemical and immunofluorescence staining were performed to detect tyrosine hydroxylase (TH) and ionized calcium binding adaptor molecule 1 (Iba-1). The expression levels of inflammatory cytokines and oxidative stress factors were detected by qPCR and ELISA. Notch signaling pathway was investigated by western blot.

Results: We found that injection of MPTP induced motor deficits in mice, enhanced the loss dopaminergic neurons and the activation of microglia, increased inflammatory and oxidative stress responses, and inhibited Notch signaling pathway. Osthole treatment suppressed theses MPTP-induced alterations.

Conclusion: In conclusion, osthole attenuates PD symptoms by suppressing Notch signaling pathway.  相似文献   

17.
18.
Parkinson's disease (PD), one of the most common neurodegenerative diseases, is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years, including alpha-synuclein, parkin, PINK1, dardarin (LRRK2), and DJ-1. DJ-1 deletions and point mutations have been found worldwide, and loss of functional protein was shown to cause autosomal recessive PD. Moreover, DJ-1 immunoreactive inclusions are found in other alpha-synucleopathies and tauopathies, indicating that different neurodegenerative diseases might share a common mechanism in which DJ-1 might play a key role. The function of DJ-1 is still unknown; however, it is associated with various cellular processes, including response to oxidative stress, cellular transformation, RNAbinding, androgen-receptor signaling, spermatogenesis, and fertilization. This article reviews the current knowledge on DJ-1, focusing on its importance in the pathogenesis of PD.  相似文献   

19.
Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease. The potential causes of PD remain uncertain, but recent studies suggest neuroinflammation and microglia activation play important roles in PD pathogenesis. Major unanswered questions include whether protein aggregates cause the selective loss of dopaminergic neurons in the substantia nigra that underlies the clinical symptoms and whether neuroinflammation is a consequence or a cause of nigral cell loss. Within the microenvironment of the brain, glial cells play a critical role in homeostatic mechanisms that promote neuronal survival. Microglia have a specialized immune surveillance role and mediate innate immune responses to invading pathogens by secreting a myriad of factors that include, cytokines, chemokines, prostaglandins, reactive oxygen and nitrogen species, and growth factors. Some of these factors have neuroprotective and trophic activities and aid in brain repair processes; while others enhance oxidative stress and trigger apoptotic cascades in neurons. Therefore, pro- and anti-inflammatory responses must be in balance to prevent the potential detrimental effects of prolonged or unregulated inflammation-induced oxidative stress on vulnerable neuronal populations. In this review, we discuss potential triggers of neuroinflammation and review the strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases. Alternatively, we propose that genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons. If chronic inflammation can be shown to decrease the levels of neuroprotective factors in the midbrain, in essence genetic haploinsufficiency of protective factors such as Parkin or RGS10 may result from purely environmental triggers (aging, chronic systemic disease, etc.), increasing the vulnerability to inflammation-induced nigral DA neuron death and predisposing an individual to development of PD. Lastly, we review the latest epidemiological and experimental evidence supporting the potential use of anti-inflammatory and immunomodulatory drugs as neuroprotective agents to delay the progressive nigrostriatal degeneration that leads to motor dysfunction in PD.  相似文献   

20.
No animal model to date perfectly replicates Parkinson's disease (PD) etiopathogenesis, and the anatomical organization of the nigrostriatal system differs considerably between species. Human postmortem material therefore remains the gold standard for both formulating hypotheses for subsequent testing in in vitro and in vivo PD models and verifying hypotheses derived from experimental PD models with regard to their validity in the human disease. This article focuses on recent and relevant fields in which human postmortem work has generated significant impact in our understanding of PD. These fields include Lewy body formation, regional vulnerability of dopaminergic neurons, oxidative/nitrative cellular stress, inflammation, apoptosis, infectious and environmental agents, and nondopaminergic lesions.  相似文献   

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