Interleukin-1β mediates sleep alteration in rats with rotenone-induced parkinsonism
Interleukin-1β mediates sleep alteration in rats with rotenone-induced parkinsonism
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DOI：
10.1093/sleep/30.4.413
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发表时间：
2007-04-01
期刊：
影响因子：
5.6
通讯作者：
Chang, Fang-Chia
中科院分区：
文献类型：
--
作者：
Yi, Pei-Lu;Tsai, Chon-Haw;Chang, Fang-Chia
研究目的：近年来，帕金森病的发病机制一直关注于小胶质细胞的激活，尤其是随后细胞因子的增加。大量临床证据表明，帕金森病患者的睡眠会发生改变；然而，对其基本的细胞机制缺乏了解。本研究旨在阐明脑白介素1β对帕金森病动物模型睡眠变化的影响，以及对多巴胺和伽马氨基丁酸(GABA)能系统的影响。设计：我们采用长期皮下注射线粒体复合体-I抑制剂鱼藤酮的方法诱导大鼠帕金森病样模型。用行为学和酪氨酸羟化酶免疫细胞化学方法证实该动物模型存在帕金森病。中枢给予药物激动剂和拮抗剂，以测试多巴胺、GABA和IL-1在鱼藤酮诱导的睡眠改变中的作用。用Western印迹和酶联免疫吸附试验检测5个不同脑区细胞因子IL-1β和肿瘤坏死因子-α的蛋白表达。地点：国立台湾大学和中国医科大学的睡眠记录仪。参与者和干预：雄性SD大鼠植入脑电电极、热敏电阻和脑室内引导管。通过在每只大鼠背部皮下植入一个阿尔茨海默病微型皮下注射鱼藤酮。测量和结果：我们发现，鱼藤酮治疗后，运动活动减少，慢波睡眠(SWS)在暗(活动)期增加，而在亮(休息)期减少，快速眼动睡眠(REM)在暗期增加。这种鱼藤酮帕金森病动物模型成功地导致黑质酪氨酸羟化酶免疫阳性神经元的丢失；诱导帕金森病患者出现的睡眠障碍事件，如白天过度嗜睡和夜间失眠；并抑制运动。我们的结果表明，脑室注射多巴胺和阻断脑内GABA对鱼藤酮诱导的睡眠改变的影响不大。提示，在目前的PD大鼠模型中，睡眠障碍主要不是由多巴胺和GABA能系统的破坏所介导的。鱼藤酮不影响肿瘤坏死因子-α的表达。然而，在鱼藤酮诱导的帕金森病大鼠中，下丘脑中IL-1β的表达增强，侧脑室注射IL-1受体拮抗剂可阻断睡眠改变而不是运动活动，提示下丘脑中IL-10的增加介导了睡眠改变，而不是运动。结论：鱼藤酮诱导的睡眠觉醒改变主要由睡眠诱导性IL-1的中枢增加所主导。
Study Objective: Recently, the pathogenesis of Parkinson disease (PD) has been focused on microglial activation, especially the subsequent increase of cytokines. A body of clinical evidence suggests that sleep is altered in patients with PD; however, there is a lack of understanding of the basic cellular mechanism. This study was designed to elucidate the influence of brain interleukin (IL)-1 beta on sleep changes, in addition to the dopaminergic and gamma-aminobutyric acid (GABA)-ergic systems, in an animal PD model.Design: We employed a long-term subcutaneous infusion of rotenone, a mitochondrial complex-I inhibitor, to induce a parkinsonism-like model in rats. Behavioral tests and tyrosine hydroxylase immunocytochemistry were used for confirmation of PD in this animal model. Pharmacologic agonist and antagonists were administered centrally to test the involvement of dopamine, GABA, and IL-1 in rotenone-induced sleep alteration. Protein expression of cytokines, ie, IL-1 beta and tumor necrosis factor alpha (TNF-alpha), in 5 distinct brain regions was also determined by Western blot and enzyme-linked immunosorbent assay (ELISA).Setting: Sleep-recording equipment in the National Taiwan University and China Medical University.Participant and Interventions: Male Sprague-Dawley rats were implanted with electroencephalogram electrodes, a thermistor, and an intracerebroventricular guide cannula. Chronic infusion of rotenone was given by an Alzet minipump implanted subcutaneously on the back of each rat.Measurement and Results: We found that locomotion activity was reduced, slow-wave sleep (SWS) was increased during the dark (active) phase and decreased during the light (rest) period, and rapid eye movement sleep (REM) was enhanced in the dark period after rotenone treatment. This rotenone PD animal model successfully causes loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra; induces the events of sleep disturbance, such as excessive daytime sleepiness and insomnia during the nighttime, that are seen in patients with PD; and suppresses locomotion. Our results that intracerebroventricular administration of dopamine and blockade of GABA in the brain have less significant effect on rotenone-induced sleep alteration suggest that the sleep disturbance is not primarily mediated by the disruption of dopaminergic and GABAergic systems in the current PD rat model. The expression of TNF-alpha was not altered by rotenone. However, the results of enhanced expression of IL-1 beta in the hypothalamus after rotenone and that of the blockade of sleep alteration, but not the locomotion activity, by intracerebroventricular administration of an IL-1 receptor antagonist implies that increased IL-1 0 in the hypothalamus mediates sleep alteration, but not the locomotion, in rats with rotenone-induced parkinsonism.Conclusion: These observations suggest that rotenone-induced sleepwake alteration is dominated by central increase of somnogenic IL-1.