Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention.
Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention.
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DOI：
10.1016/j.nbd.2009.11.004
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发表时间：
2010-03
影响因子：
6.1
通讯作者：
Goldberg MS
中科院分区：
文献类型：
--
作者：
Tansey MG;Goldberg MS
帕金森病 (PD) 是继阿尔茨海默病之后第二常见的神经退行性疾病。 PD 的潜在原因仍不确定，但最近的研究表明神经炎症和小胶质细胞激活在 PD 发病机制中发挥重要作用。主要未解答的问题包括蛋白质聚集体是否导致黑质中多巴胺能神经元的选择性丧失，而黑质中的多巴胺能神经元是临床症状的基础，以及神经炎症是黑质细胞损失的结果还是原因。在大脑微环境中，神经胶质细胞在促进神经元存活的稳态机制中发挥着关键作用。小胶质细胞具有专门的免疫监视作用，通过分泌多种因子（包括细胞因子、趋化因子、前列腺素、活性氧和氮以及生长因子）来介导针对入侵病原体的先天免疫反应。其中一些因子具有神经保护和营养活性，有助于大脑修复过程；而另一些则增强氧化应激并引发神经元的凋亡级联反应。因此，促炎反应和抗炎反应必须保持平衡，以防止长期或不受调节的炎症诱导的氧化应激对脆弱神经元群产生潜在的有害影响。在这篇综述中，我们讨论了神经炎症的潜在触发因素，并回顾了最有力的直接证据，表明慢性神经炎症可能在帕金森病中比其他神经退行性疾病发挥更重要的作用。或者，我们认为遗传缺陷并不是减少大脑保护因子的唯一方法，这些保护因子可能起到控制小胶质细胞反应或调节 DA 神经元敏感性的作用。如果慢性炎症能够降低中脑神经保护因子的水平，那么本质上，Parkin 或 RGS10 等保护因子的遗传单倍体不足可能是由纯粹的环境触发因素（衰老、慢性全身性疾病等）引起的，从而增加了炎症引起的黑质 DA 神经元死亡的脆弱性，并使个体易患 PD。最后，我们回顾了最新的流行病学和实验证据，支持抗炎和免疫调节药物作为神经保护剂的潜在用途，以延缓导致帕金森病运动功能障碍的进行性黑质纹状体变性。
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.
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DOI：
10.1073/pnas.0400569101
发表时间：
2004-06-22
影响因子：
11.1
作者：
Benner, EJ;Mosley, RL;Gendelman, HE
通讯作者：
Gendelman, HE
影响因子：
4.8
作者：
Delgado, M;Ganea, D
通讯作者：
Ganea, D
影响因子：
15.9
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
通讯作者：
Hunot, Stephane
影响因子：
3.7
作者：
Benner EJ;Banerjee R;Reynolds AD;Sherman S;Pisarev VM;Tsiperson V;Nemachek C;Ciborowski P;Przedborski S;Mosley RL;Gendelman HE
通讯作者：
Gendelman HE
DOI：
10.1006/neur.1996.0020
发表时间：
1996-06-01
期刊：
NEURODEGENERATION
影响因子：
--
作者：
Czlonkowska, A;Kohutnicka, M;Czlonkowski, A
通讯作者：
Czlonkowski, A