探討中草藥純物質 PN 衍生物作為治療阿茲海默氏症藥物之開發與機轉

Abstract

阿茲海默症 (Alzheimer’s disease, AD)是常見的神經退化性疾病之一， 罹患的人數隨著人口邁向高齡化社會而逐漸增加，患者會有記憶、學習以及語言能力的缺失。 為了開發治療藥物，我們之前利用 DiBAC4(3)膜電位螢光染劑， 篩選可以減緩 Aβ 寡聚體誘導神經細胞發生不正常去極化的純物質， 藉此平台得到一種源自白芍中草藥的純物質，暫時命名為 PN，已發現 PN 會透過調節NMDA receptor 減緩 Aβ 寡聚體所導致的神經細胞不正常去極化。 本研究旨在以 PN 為基底尋找有效或更有效之 PN 衍生物。 目前階段篩選了 6 種 PN 衍生物暫時命名為 PN1~PN6，發現其中的 PN4 可以改善 Aβ 寡聚體所誘導的神經細胞不正常去極化， PN4 具有類似 AMPA 受體拮抗劑以及 NMDA 受體拮抗劑的特性，可以改善 AMPA 及 NMDA 所導致的神經細胞不正常去極化， 藥物機轉則發現 PN4 能降低 Aβ 寡聚體以及 NMDA 所誘發之上升的磷酸化 ERK 分子；使用阿茲海默症模式小鼠 J20， 以皮下注射方式給予小鼠 PN4， 其對於小鼠的基本生理參數像是體重、發炎指標 GOT、 GTP 以及肝腎組織切片觀察， 皆不會有不良影響， 進一步在動物行為方面發現， 模式小鼠在給予 PN4 後，其在巴恩斯迷宮所檢測之學習記憶以及新物體辨識之辨識記憶並無改善效果，但在莫氏水迷津所檢測之長期空間記憶方面則有顯著的改善。 綜合以上， PN4 可能透過拮抗 AMPA 受體以及 NMDA 受體， 藉以減緩 Aβ 寡聚體所導致的神經細胞不正常去極化，且改善阿茲海默症模式小鼠 J20 長期記憶缺失的現象， 希望最終能開發一種對於治療阿茲海默症患者有所助益的藥物。The number of people affected Alzheimer’s disease (AD), a progressive neurodegenerative disease, gradually increases as the population moves toward an aging society. AD leads to memory, learning, and language impairment. In order to develop therapeutic drugs, we have established a drug screening platform in which Aβ oligomers induce abnormal depolarization of neurons. We found a herbal extract pure compound, named PN, is able to ameliorate Aβ-induced depolarization. In this study, we further screen 6 PN-derived compounds to examine whether or not any of these derivatives can be the same and/or more effective than PN. Thus far, we found PN4 which can ameliorate Aβ-induced depolarization. It could mediate AMPA receptors and NMDA receptors to execute such effects. In the molecular mechanism, PN4 could inhibit the increased phosphorylation of ERK signaling molecule induced by Aβ or NMDA. In the animal experiments, the body weight, GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), and histology of liver and kidney tissues show no change in the J20 mice versus wild type after PN4 treatment. In the learning and memory behavior test, PN4 has no effect on the learning and memory of J20 mice in barnes maze and new object recognition tests. However, PN4 given to J20 mice could significantly improve the long-term memory behavior in the Morris water maze test. Taken together, PN4 could ameliorate Aβ-induced depolarization by antagonizing AMPA receptors and NMDA receptors as well as improve learning and memory in AD mouse model. Hopefully, this compound might be developed to be eventually beneficial on treatment of AD patients.