中草藥純物質 Baicalein 衍生物作為治療阿茲海默氏症藥物開發之探討

Abstract

阿茲海默氏症為目前高齡社會中常見的退化性疾病之一，病患會出現神經損傷與 記憶上的缺陷，已知 β-類澱粉蛋白 (amyloid-β, Aβ) 的堆積以及 tau 蛋白的過度磷酸化為 阿茲海默氏症的兩個重要病理特徵，Aβ 的堆積會導致麩胺酸在神經突觸間的過量，此 變化進一步引發神經細胞的死亡。先前實驗室研究中利用初級培養的小鼠大腦皮質神 經細胞和一種檢測膜電位變化的螢光染劑 DiBAC4(3)，建立藥物篩選的平台，旨在篩 選出能夠改善 Aβ 所引發的神經異常去極化的中草藥，已發表中草藥黃芩所含有的黃芩素 (Baicalein, BE) 能夠有效的抑制 Aβ 對神經所造成的影響，本研究旨在找到更有效力 之黃芩素衍生物，期望能夠為阿茲海默氏症病患的治療藥物之發展上有所貢獻。結果 顯示在六種黃芩素衍生物中篩選到其中一衍生物具有較強的效果，暫時命名為 BE2， 發現 BE2 可能透過作用於 AMPA 和 NMDA 兩種麩胺酸接受器來降低 Aβ 所造成的神經 不正常去極化反應。進一步研究，發現 BE2 能夠抑制 NMDA 所造成的細胞鈣離子流入 的現象，並且能夠抑制在初級培養的大腦皮質神經細胞中給予 Aβ 或 NMDA 刺激後所 造成的 Erk 活化的現象。另外將 BE2 以皮下注射方式給予阿茲海默氏症模式鼠 J20 ， 發現此種純物質對於小鼠體重、發炎指標 GOT 與 GPT 以及組織切片觀察等基本檢測並 不會造成影響，但在行為實驗中則發現注射 BE2 的 J20 小鼠在莫氏水迷津實驗、與新 物體識別實驗中能夠有效改善空間記憶與認知能力。綜合以上黃芩素衍生物 BE2 極具作為阿茲海默氏症治療藥物之潛力。

Alzheimer's disease is one of the most common neurodegenerative diseases. Two important pathological hallmarks of Alzheimer's disease include the presence of amyloid-β (Aβ) plaque and tau protein hyperphosphorylation in brain tissue. Utilizing mouse primary cortical neurons and DiBAC4(3), a slow- response voltage sensitive fluorescence, we have set up a drug screening system and found a herbal extraction Baicalein (BE) which can ameliorate the abnormal depolarization induced by Aβ oligomers. Inthis study, we aim to find a more effective BE derivatives. Currently, we found that one out of six BE derivatives, temporarily named it BE2, is able to ameliorate the abnormal depolarization induced by Aβ oligomers in which it might be via the inhibition of AMPAR and NMDAR. In the regard of the molecular mechanism, BE2 inhibits the influx of calcium induced by NMDA. The increased phosphorylation of Erk caused by Aβ oligomers and NMDA in primary cultured cortical neurons is reversed by BE2 treatment. Furthermore, J20, an Alzheimer's disease mice model, is adopted to examine the effect of BE2 on animal level. J20 mice injected with BE2 could effectively improve spatial memory and cognitive ability in the Morris water maze test and novel object recognition test. Taken together, the BE derivative BE2 could be a potential compound developed as a therapeutic drug for Alzheimer's disease.