高壓氧對第十七型脊髓小腦運動失調症小鼠的治療效果

The effect of hyperbaric oxygen on SCA17 mice

江孟格(Chiang Meng-Ke)

指導教授 ： 謝秀梅

國立臺灣師範大學/理學院/生命科學系/碩士(2019年)

https://doi.org/10.6345/NTNU201900438

摘要

第十七型脊髓小腦運動失調症 (SCA17) 是一種體染色體顯性遺傳神經退化性疾病，患者有漸進式的小腦萎縮、共濟失調、癲癇及認知障礙等病徵。然而，目前沒有任何具有顯著療效的藥物可以治療SCA17。本研究旨在探討高壓氧治療(HBOT)對SCA17 TG小鼠行為改善及神經保護的作用。HBOT是一種無痛、較為非侵入性的治療方式，患者於充滿100%氧氣且高壓的艙室中進行治療；目前已知可用於治療一氧化碳中毒、動脈栓塞、創傷性腦損傷、燒燙傷及減壓病(潛水夫病)等；目前已有文獻證實，HBOT可以降低發炎反應的發生、改善組織缺氧的狀態，並促使微血管增生。本研究採用SCA17基因轉殖小鼠，進行各式行為實驗(曠野實驗、Ｙ字迷宮、步態分析及滾輪測試)評估其運動和空間記憶的能力；經過HBOT，我們發現SCA17 TG小鼠的焦慮情況、短期記憶及運動協調能力有顯著地改善。我們也以每個月進行一次行為實驗之方式得知HBOT效果的持續性可以維持三個月。而輕微高壓氧(M-HBOT)能夠使小鼠短期記憶及運動協調能力有顯著地改善。在小腦組織病理切片結果中，我們發現，HBOT降低了SCA17 TG小鼠小腦中Purkinje cell丟失，也使其排列順序變整齊、細胞本體較為飽滿及神經纖維密度上升；也發現HBOT能夠抑制SCA17 TG小鼠減緩其神經發炎反應astrocyte及microglia的發生；另外，經HBOT之SCA17 TG小鼠與記憶相關及細胞增殖之蛋白路徑AKT/CaMKII -ERK-CREB在小腦中磷酸化之蛋白表現量有顯著的上升。因此，我們認為研究結果說明HBOT對於SCA17具有治療的發展潛力。

關鍵字

第十七型脊髓小腦運動失調症 ； 基因轉殖小鼠 ； 高壓氧治療

並列摘要

Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant inherited neurodegenerative disease. Patients show progressive cerebellar atrophy, ataxia, epilepsy and dementia. However, no drug with significant effect on the treatment of SCA17 has been developed. This study was designed to investigate the effects of hyperbaric oxygen therapy (HBOT) on neuroprotection in SCA17 TG mice. HBOT is a painless, less-invasive treatment that is widely used for carbon monoxide poisoning, arterial embolism, traumatic ischemia, burns and decompression sickness. Patients are treated in a cabinet with high atmospheric pressure and 100% oxygen for a period of time. It is reported HBOT reduces the inflammatory re-sponse and hypoxia in tissue, and improves microvascular proliferation. In this study, behavior tests on SCA17 transgenic mice were performed before and after HBOT, including the open-field, Y-maze, footprint and rotarod. The results showed that HBOT had no effect in the improvement of hyperactivity and gait ataxia according to the open-field and footprint tests, while the results from open-field, Y-maze and rotarod tests showed HBOT significantly improved the anxiety, short-term memory and motor-coordination of SCA17 mice. After the monthly behavioral evaluation, we learned that the duration of this HBOT effect can be lasted for three months. However, mild hyperbaric oxygen (M-HBOT) can only significantly improve short-term memory and motor coordination in SCA17 mice. Therefore, we believed that HBOT has therapeutic potential for SCA17. In the pathological examination of cerebellum, we found that HBOT reduced the loss of Purkinje cells in the cerebellum of SCA17 TG mice, made the cells in a more order pattern, enlarged the cell body , and the increased the nerve fiber density. It was also found that HBOT ameliorated the neuroinflammatory response of SCA17 mice. In addition, the HBOT increased the proteins associated with memory pathway, AKT/CaMKII, ERK, and CREB in the mouse cerebellum. These findings suggest that HBOT has therapeutic potential for SCA17.

並列關鍵字

Spinocerebellar ataxia type 17 ； transgenic mice ； hyperbaric oxygen therapy

參考文獻

Araujo, J., P. Breuer, S. Dieringer, S. Krauss, S. Dorn, K. Zimmermann,

A. Pfeifer, T. Klockgether, U. Wuellner and B. O. Evert (2011). "FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3." Hum. Mol. Genet. 20(15): 2928-2941.

Asano, T., E. Kaneko, S. Shinozaki, Y. Imai, M. Shibayama, T. Chiba,

M. Ai, A. Kawakami, H. Asaoka and T. Nakayama (2007). "Hyperbaric oxygen induces basic fibroblast growth factor and hepatocyte growth factor expression, and enhances blood perfusion and muscle regeneration in mouse ischemic hind limbs." Circ. J. 71(3): 405-411.

Barnham, K. J., C. L. Masters and A. I. Bush (2004). "Neurodegenerative