以大鼠模式探討帕金森症患者睡眠失常之機轉

帕金森氏症 (Parkinson’s Disease, PD) 於1817年由英國的帕金森醫師發表的病例報告之後，世人開始注意到這些患者。在許多人投入帕金森的研究之後，針對帕金森症患者的大腦進行種種實驗，發現患者腦中紋狀體 (striatum) 的多巴胺含量顯著少於正常人，進一步分析則發現，多巴胺減少是由於患者黑質 (substantia nigra, SN) 所存活分泌多巴胺的神經元大量減少，並由此結果得知帕金森患者所出現的眾多症狀皆起因於此。本研究關心的重點在帕金森患者所產生的睡眠症狀上，這個部分較不為一般人所重視，有許多症狀產生的機轉仍待研究人員進一步了解。我們試著將藥物直接施打於大鼠大腦黑質處，阻斷黑質附近ubiquitin-proteasome system之功能，造成被ubiquitin結合的蛋白質無法經由proteasome分解而大量堆積於位在黑質的多巴胺神經元，而使微膠細胞 (microglia cell) 活化，造成多巴胺神經活性衰退，大鼠上產生類似PD患者的睡眠障礙症狀，並藉由此模式來探討PD患者睡眠產生改變的機轉是否經過微膠細胞活化所釋放之細胞素 (cytokine) 而造成。 MG-132 (proteasome inhibitor) 施打之後，apomorphine (多巴胺的作用劑) 的測試的確能觀察到大鼠原地轉圈的數目在給予後有增加的現象，證明多巴胺神經元的確有減少釋出多巴胺的情形，並且能產生大鼠的運動障礙。我們分析大鼠EEG的變化，發現MG-132施打後一週，大鼠的睡眠便產生了在活動期睡眠增加，但在睡眠期之睡眠有減少的變化，這與PD患者所產生的睡眠障礙相當類似。此變化經由tumor necrosis factor receptor fragment (TNFRF) 、或是nuclear factor-kappa B (NF-κB) inhibitor的施打，都能令其回復至與控制組接近的睡眠量，而interlukin-1 receptor antagonist (IL-1ra) 對MG-132所造成的增加在大鼠活動期睡眠現象卻無法產生顯著的抑制作用。理論上MG-132的施予能造成大鼠腦中IL-1β及TNF-α在特定幾個影響睡眠的腦區中含量增加，實際上MG-132的確使中腦及下視丘TNF-α的表現量增加，NF-κB的表現也因為MG-132的施打，可看到紋狀體 (striatum) 所偵測到NF-κB有明顯增加活化的情形，而IL-1β的表現在MG-132給予之後並沒有看到顯著的增加。由此可推論，MG-132所導致的睡眠失調，是經過TNF-α-NF-κB這條路徑的改變所造成，而非IL-1β。

關鍵字

帕金森氏症；腦波圖；睡眠；細胞素； NF-κB ； MG-132 ； ubiquitin-proteasome system

並列摘要

For patients with the Parkinson’s disease (PD), the degeneration of dopaminergic neurons causes the decrease of dopamine release from the substantia nigra pars compecta (SNpc) to the striatum. It is also found that the PD patient’s brain has inclusion bodies of α-synuclein in this area. These inclusion bodies can lead to activate mitochondrial and to subsequently release cytokines, such as tumor necrosis factor – alpha (TNF-α) and interlukin-1beta (IL-1β), which affect the PD patient’s sleep. We herein used a proteasome inhibitor, MG-132, to inhibit the function of proteasome, which caused the loss of dopaminergic neurons in SNpc, and subsequently changed the sleep architecture in rats. The total amount of NREMS was significantly increased, and the of wakefulness was decreased during the dark-period at the 7th day after MG-132 treatment. We administered tumor necrosis factor receptor fragment (TNFRF) and interlukin-1 receptor antagonist (IL-1ra), to elucidate the involvement of TNF-α and IL-1β in MG-132-induced sleep alteration. The MG-132-induced sleep alteration was reversed after giving those blockers of cytokines. We employed BAY11-7085 and SN50, the nuclear factor-kappa B (NF-κB) inhibitors, to verify the involvement of NF-κB activation. Out results indicated that NF-κB inhibitor also blocked MG-132-induced sleep disturbance. The expression of TNF-α was increase after MG-132 administration, but there has no alteration on IL-1β expression. The activation of NF-κB at the striatum was significantly increased after injection of the MG-132. In this study, we demonstrated that TNF-NF-κB pathway is involved in the mechanism of sleep disturbance in rats with MG-132-induced parkinsonism.

並列關鍵字

electroencephalograph (EEG) ； sleep ； cytokines ； NF-κB ； MG-132 ； ubiquitin-proteasome system

參考文獻

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以大鼠模式探討帕金森症患者睡眠失常之機轉

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