開發脂氧脢抑制劑於治療腦中風與巴金森氏症之應用

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Title:	開發脂氧脢抑制劑於治療腦中風與巴金森氏症之應用
Authors:	劉宏輝;侯曼貞(Hour, Mann-Jen)
Contributors:	藥學院藥學系
Date:	2012-07-31
Issue Date:	2012-06-15 11:44:00 (UTC+8)
Abstract:	先前計畫中我們以MJ-39 為先導化合物，因其在大鼠腦中風模式下，能有效減少中樞神經損傷，並且能提高老鼠中風後的運動能力，且在離體與活體實驗中皆表現出拮抗 MPP+造成的中樞神經毒性；經MDS 的基礎藥理篩選後，發現其是專一有效的5-LOX 及15-LOX 抑制劑。在相關論文檢索上發現，5-LOX 抑制劑在大鼠腦中風模式下已被報告，可以有效的保護中風後的神經元；而15-LOX 的基因剔除小鼠也能有效減低中風後大腦神經損傷；近期更發現15-LOX 抑制劑能降低氧化壓力，因此被認為可能具有治療巴金森氏症潛力。在治療中風與巴金森氏症的藥物發展，雖然各大藥廠皆投入心血研發，但是進入臨床試驗的藥品數量並不多，因此我們選定以治療此疾病的藥物研發為目標。由於MJ-39 經過檢索後，該化合物已被揭露，因此之後又經由實驗篩選MJ-39 之其他衍生物，目前已發展出具有高度開發價值的新穎化合物CTS-12。我們先以中腦神經與神經膠細胞來測試CTS-12 對MPP+所造成的神經毒性影響，發現其仍然具有不錯的保護效果；而在動物實驗方面，亦能保護中風老鼠大腦皮質的損傷，並能拮抗MPTP 造成多巴胺神經元的損傷。此外，我們自美國Jackson Lab 引進15-LOX 基因剔除小鼠，藉由此實驗動物，來釐清15-LOX 在巴金森氏症中的角色，初步實驗顯示15-LOX knockout mice 可以減少MPTP 毒性。綜合以上結果，我們將以基礎與臨床研究為基石，一步一步的完成我們的計畫目標 (1) 深入研究CTS-12 對中風以及巴金森氏症的治療效果。(第一~二年) (2) 我們會利用computer modeling 來找出更多相似的化合物，目前已模擬出二十多個新的化合物，期望未來能夠合成一系列治療中風與巴金森氏症的藥物。(第一~二年) (3) 將進一步探討在動物實驗及細胞實驗增加CTS-12 的功能性實驗及相關機轉之探討。(第一~二年) (4) 除了中風與巴金森氏症外，我們期望以CTS-12 系列化合物，再增加探索其治療其他神經退化疾病如:老年失智症的可行性。(第三年) 因此我們認為CTS-12 具有作為治療中風與巴金森氏症藥物的潛力，將於近日提出美國臨時性的專利，期望未來能夠合成一系列治療中風與巴金森氏症的藥物。 Since 2002, we have used the mice stroke model to screen over 1000 compounds. The most effective pure compound among all samples was the molecular with code number of MJ-39. Treatment with MJ-39 protected the brain from infarction in rats after ischemia/reperfusion (I/R) injury. The biochemical screen assay results from MDS show that MJ-39 is a potent and specific inhibitor for both 5-lipoxygenase (5-LOX) and 12/15-lipoxygenase (12/15-LOX). A number of studies have indicated that leukotrienes derived from 5-LOX cause inflammation and are involved in pathobiology of neurodegeration diseases. Since the MJ-39 is not a new compound, we then screen more related compound and found a more effective derivative than MJ-39. This new compound entity, CTS-12, protected the brain from damage following ischemia/reperfusion of MCA in rat and significantly increased the dopaminergic neurons number in mesencephalic neuron-glia co-cultures after MPP+ treatment. Furthermore, CTS-12 inhibits MPTP-induced decrease of dopamine contents in striatum in mice. These experiments have highlighted that LOXs may play an important role in the pathology of stroke and Parkinson’s disease. We plan to achieve our goal by addressing the following aims, based on relevantly basic or clinical evidence and our preliminary results. (1) To focus on the lead CTS-12-related compounds for the treatment of stroke and Parkinson’s disease. (year 1-2) (2) We have got several new compounds from computer modeling system. These compounds will be synthesized by co-PI and we will evaluate its efficacy in neuroprotection both in vitro and in vivo. (year 1-2) (3) To explore the action mechanism of CTS-12-related compounds for the treatment of stroke and Parkinson’s disease. (year 1-2) (4) Further studies of these novel neuroprotective actions of LOXs inhibitors may provide new therapeutic opportunities to treat other neurodegenerative diseases, such as Alzheimer's disease. (year 3) Therefore, CTS-12 is a potent lead compound for the development of new category of drug to treat stroke and Parkinson’s disease.CTS-12 and its related compounds will be filed provisional patent (in USA) recently. Thus, our findings will reveal the role of lipoxygenase in pathology of stroke and Parkinson's disease. On the other hand, these results will offer a new therapeutic strategy to treat those neurodegenerative diseases.
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