Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease.
Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease.
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中枢和全身IL-1加剧了帕金森氏病模型中的神经变性和运动症状。
DOI：
10.1093/brain/awn101
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Pitossi FJ
中科院分区：
文献类型：
--
作者：
Pott Godoy MC;Tarelli R;Ferrari CC;Sarchi MI;Pitossi FJ
帕金森病是一种病因不明、病理生理学不清的神经退行性疾病。黑质（SN）中的活化小胶质细胞在帕金森病的所有动物模型和患有该疾病的患者中均被发现。然而，小胶质细胞可能在这种疾病中具有有害和保护功能。在这项研究中，我们测试了亚毒性剂量的致炎原（脂多糖）可以将小胶质细胞转变为促炎状态并加剧帕金森病动物模型中的疾病进展的假设。在变性SN中的中枢脂多糖注射加剧了神经变性，加速和增加了运动体征，并将小胶质细胞活化转变为促炎表型，同时增加了白细胞介素-1 β（IL-1β）分泌。糖皮质激素治疗和特异性IL-1抑制逆转了这些作用。重要的是，IL-1的慢性全身表达也加剧了SN中的神经变性和小胶质细胞活化。在体外，IL-1直接加重6-OHDA触发的多巴胺能毒性。在体内，我们发现一氧化氮是IL-1作用的下游分子，并部分负责观察到的神经退行性变的恶化。因此，IL-1通过直接和间接机制对变性的多巴胺能神经元发挥其加重作用。这项工作证明了IL-1过度产生与疾病进展增加之间的明确关联，指出炎症是帕金森病的危险因素，并表明应有效地处理患者的炎症以减缓疾病进展。
Parkinson's disease is a neurodegenerative disorder with uncertain aetiology and ill-defined pathophysiology. Activated microglial cells in the substantia nigra (SN) are found in all animal models of Parkinson's disease and patients with the illness. Microglia may, however, have detrimental and protective functions in this disease. In this study, we tested the hypothesis that a sub-toxic dose of an inflammogen (lipopolysaccharide) can shift microglia to a pro-inflammatory state and exacerbate disease progression in an animal model of Parkinson's disease. Central lipopolysaccharide injection in a degenerating SN exacerbated neurodegeneration, accelerated and increased motor signs and shifted microglial activation towards a pro-inflammatory phenotype with increased interleukin-1β (IL-1β) secretion. Glucocorticoid treatment and specific IL-1 inhibition reversed these effects. Importantly, chronic systemic expression of IL-1 also exacerbated neurodegeneration and microglial activation in the SN. In vitro, IL-1 directly exacerbated 6-OHDA-triggered dopaminergic toxicity. In vivo, we found that nitric oxide was a downstream molecule of IL-1 action and partially responsible for the exacerbation of neurodegeneration observed. Thus, IL-1 exerts its exacerbating effect on degenerating dopaminergic neurons by direct and indirect mechanisms. This work demonstrates an unequivocal association between IL-1 overproduction and increased disease progression, pointing to inflammation as a risk factor for Parkinson's disease and suggesting that inflammation should be efficiently handled in patients to slow disease progression.
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