Department of Anatomy and Neurobiology, University of Kentucky, Medical Center, KY 40536, USA; Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
Neurobiol Aging. 2007 Jun;28(6):894-906. doi: 10.1016/j.neurobiolaging.2006.04.011.
Inflammation has been increasingly recognized to play an important role in the pathogenesis of Parkinson's disease (PD). Using immunocytochemistry and electron microscopy, we found that intranigral injection of lipopolysaccharide (LPS) caused marked microglial activation and a dose-dependent selective loss of dopaminergic neurons, which was mediated by apoptosis as evidenced by prominent TUNEL labeling. RNase protection assays revealed that mRNA for Bax, Fas and the pro-inflammatory cytokines interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor (TNF)-α were significant increased ipsilaterally in LPS-injected side of SN, while expression of the anti-apoptotic gene Bcl-2 was decreased. Osmotic pump infusion of IL-10, a global inhibitor of cytokine synthesis, protected against LPS-induced cell death of dopaminergic neurons, with a corresponding decrease in the number of activated microglia, suggesting that the reduction in microglia-mediated release of inflammatory mediators may contribute to the anti-inflammatory effect of IL-10. Our results provide evidence that LPS induces apoptotic cell death in SNpc, which is likely through the expression of Fas, Bax, caspase-3, and the pro-inflammatory cytokines.
炎症在帕金森病（PD）的发病机制中起着重要作用，这一点已得到越来越多的认识。通过免疫细胞化学和电子显微镜检查，我们发现向黑质内注射脂多糖（LPS）会导致明显的小胶质细胞激活，并伴有多巴胺能神经元的剂量依赖性选择性丧失，这是由凋亡介导的，凋亡的证据是 TUNEL 标记明显。RNA 保护分析显示，Bax、Fas 和促炎细胞因子白细胞介素（IL）-1α、IL-1β、IL-6 和肿瘤坏死因子（TNF）-α 的 mRNA 在 LPS 注射侧 SN 的同侧显著增加，而抗凋亡基因 Bcl-2 的表达减少。IL-10 的渗透泵输注，一种细胞因子合成的全局抑制剂，可防止 LPS 诱导的多巴胺能神经元死亡，同时激活的小胶质细胞数量减少，这表明小胶质细胞介导的炎症介质释放减少可能有助于 IL-10 的抗炎作用。我们的研究结果提供了证据，表明 LPS 在 SNpc 中诱导凋亡性细胞死亡，这可能是通过 Fas、Bax、半胱天冬酶-3 和促炎细胞因子的表达来实现的。
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