Department of Pharmacology, Toxicology and Therapeutics, Division of Toxicology, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
J Neuroinflammation. 2013 Dec 1;10:143. doi: 10.1186/1742-2094-10-143.
Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder caused by selective loss of dopaminergic neurons from the substantia nigra (SN) to the striatum. The initial factor that triggers neurodegeneration is unknown; however, inflammation has been demonstrated to be significantly involved in the progression of PD. The present study was designed to investigate the role of the pro-inflammatory cytokine interleukin-1 (IL-1) in the activation of microglia and the decline of motor function using IL-1 knockout (KO) mice.
Lipopolysaccharide (LPS) was stereotaxically injected into the SN of mice brains as a single dose or a daily dose for 5 days (5 mg/2 ml/injection, bilaterally). Animal behavior was assessed with the rotarod test at 2 hr and 8, 15 and 22 days after the final LPS injection.
LPS treatment induced the activation of microglia, as demonstrated by production of IL-1β and tumor necrosis factor (TNF) α as well as a change in microglial morphology. The number of cells immunoreactive for 4-hydroxynonenal (4HNE) and nitrotyrosine (NT), which are markers for oxidative insults, increased in the SN, and impairment of motor function was observed after the subacute LPS treatment. Cell death and aggregation of α-synuclein were observed 21 and 30 days after the final LPS injection, respectively. Behavioral deficits were observed in wild-type and TNFα KO mice, but IL-1 KO mice behaved normally. Tyrosine hydroxylase (TH) gene expression was attenuated by LPS treatment in wild-type and TNFα KO mice but not in IL-1 KO mice.
The subacute injection of LPS into the SN induces PD-like pathogenesis and symptoms in mice that mimic the progressive changes of PD including the aggregation of α-synuclein. LPS-induced dysfunction of motor performance was accompanied by the reduced gene expression of TH. These findings suggest that activation of microglia by LPS causes functional changes such as dopaminergic neuron attenuation in an IL-1-dependent manner, resulting in PD-like behavioral impairment.
帕金森病（PD）是一种与年龄相关的进行性神经退行性疾病，由黑质（SN）到纹状体的多巴胺能神经元选择性丧失引起。触发神经退行性变的初始因素尚不清楚；然而，炎症已被证明在 PD 的进展中起着重要作用。本研究旨在使用白细胞介素-1（IL-1）基因敲除（KO）小鼠研究促炎细胞因子白细胞介素-1（IL-1）在小胶质细胞激活和运动功能下降中的作用。
将脂多糖（LPS）立体定向注射到小鼠脑的 SN 中，单次剂量或每天剂量 5 天（5mg/2ml/注射，双侧）。最后一次 LPS 注射后 2 小时和 8、15 和 22 天，通过转棒试验评估动物行为。
LPS 处理诱导小胶质细胞激活，表现为产生白细胞介素-1β和肿瘤坏死因子（TNF）α以及小胶质细胞形态改变。SN 中 4-羟基壬烯醛（4HNE）和硝基酪氨酸（NT）免疫反应性细胞的数量增加，这是氧化损伤的标志物，并且在亚急性 LPS 处理后观察到运动功能障碍。在最后一次 LPS 注射后 21 天和 30 天分别观察到细胞死亡和α-突触核蛋白聚集。在野生型和 TNFα KO 小鼠中观察到行为缺陷，但 IL-1 KO 小鼠行为正常。LPS 处理减弱了野生型和 TNFα KO 小鼠中酪氨酸羟化酶（TH）基因的表达，但在 IL-1 KO 小鼠中没有。
SN 中 LPS 的亚急性注射会导致小鼠出现类似 PD 的发病机制和症状，包括α-突触核蛋白的聚集。LPS 诱导的运动功能障碍伴随着 TH 基因表达的减少。这些发现表明，LPS 激活小胶质细胞以 IL-1 依赖性方式引起功能变化，如多巴胺能神经元衰减，导致类似 PD 的行为损伤。
