Institute Leloir Foundation and IIBBA-CONICET, Patricias Argentinas 435, Buenos Aires, Argentina.
Neurobiol Dis. 2010 Mar;37(3):630-40. doi: 10.1016/j.nbd.2009.11.018. Epub 2009 Dec 5.
Inflammation, and in particular microglia activation, is regarded as a constant component of brain pathology in Parkinson's disease (PD). Microglial activation has been found in the substantia nigra (SN), one of the main brain regions affected in PD, for many years after the initiation of the disease. Although many studies point towards a deleterious role of inflammation on PD, the functional role of many of its main components has not been clarified yet. For example, tumor necrosis factor-alpha (TNF-alpha), a key pro-inflammatory cytokine, has been shown to exert toxic or no effects on the viability of dopaminergic neurons. No study has evaluated the effects of the long-lasting TNF-alpha expression in the SN, an experimental set-up most probably resembling the clinical situation. The aim of this study was to investigate the effects of the chronic expression of TNF-alpha in the adult SN at different time points. Adenoviral expression of low TNF-alpha levels (17-19 pg/mg) lasted for 14 days in the SN and did not induce interleukin-1beta (IL-1beta) expression. Long-lasting TNF-alpha expression caused dopaminergic cell death from day 14, increasing at 21 and 28 days compared with control animals injected with adenovectors expressing beta-galactosidase. TNF-alpha overexpression elicited irreversible, unilateral akinesia starting at 14 days, but not earlier. These effects were accompanied by microglial activation to stage 4 and/or monocyte/macrophage recruitment from the periphery from day 7 post adenovector inoculations. Thus, we conclude that extended duration of the expression of TNF-alpha is necessary and sufficient for a univocal toxic effect of TNF-alpha on dopaminergic neurons and motor disabilities. This study provides an animal model to study early events that lead to TNF-alpha-mediated neuronal demise in the SN. In addition, the cellular components of the inflammation elicited by TNF-alpha and the lack of IL-1beta expression support the growing idea of a distinct cytokine network in the brain.
炎症，特别是小胶质细胞的激活，被认为是帕金森病 (PD) 脑病理学的一个持续组成部分。多年来，小胶质细胞的激活一直存在于 PD 主要受影响的大脑区域之一的黑质 (SN) 中。尽管许多研究表明炎症对 PD 有有害作用，但它的许多主要成分的功能作用尚未阐明。例如，肿瘤坏死因子-α (TNF-α)，一种关键的促炎细胞因子，已被证明对多巴胺能神经元的存活有有毒或无影响。没有研究评估 TNF-α在 SN 中的长期表达的影响，这种实验设置最可能类似于临床情况。本研究旨在研究 TNF-α在 SN 中的慢性表达在不同时间点对成年 SN 的影响。低 TNF-α水平 (17-19 pg/mg) 的腺病毒表达在 SN 中持续 14 天，不会诱导白细胞介素-1β (IL-1β) 的表达。长期 TNF-α表达导致多巴胺能神经元从第 14 天开始死亡，与注射表达β-半乳糖苷酶的腺病毒载体的对照动物相比，21 天和 28 天增加。TNF-α过表达从第 14 天开始引起不可逆转的单侧运动不能，但更早不会。这些影响伴随着小胶质细胞激活到第 4 阶段和/或单核细胞/巨噬细胞从外周募集，从腺病毒接种后第 7 天开始。因此，我们得出结论，TNF-α表达的延长时间是 TNF-α对多巴胺能神经元和运动障碍产生明确毒性作用的必要和充分条件。这项研究提供了一个动物模型，用于研究导致 TNF-α介导的 SN 中神经元死亡的早期事件。此外，TNF-α引起的炎症的细胞成分和缺乏 IL-1β的表达支持了大脑中独特的细胞因子网络的不断发展的观点。
