鑑定新藥物NCT016以治療阿茲海默症
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2015
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阿茲海默症（Alzheimer’s disease）是漸進性的神經退化性疾病，其病徵包括漸進性的記憶能力損失以及在大腦皮質和海馬迴等區域有類澱粉斑塊（amyloid plaque）產生。膽鹼性假說（cholinergic hypothesis）說明乙醯膽鹼（acetylcholine）的濃度下降會導致認知與記憶能力的損失。先前的研究顯示，當抑制乙醯膽鹼酯酶（acetylcholinesterase），水解乙醯膽鹼的酵素，可以提升腦部乙醯膽鹼的濃度，而改善AD病人腦中膽鹼神經（cholinergic neuron）之間的訊息傳導。目前用於治療AD的藥物當中乙醯膽鹼酯酶抑制劑仍佔有一席之地，其可改善病徵以及認知功能。所以本篇研究目的在於鑑定黃芩萃取物NCT016是否可以有效抑制乙醯膽鹼酯酶的活性來保護神經細胞的新穎藥物。本實驗使用的細胞模式是Tet-On Aβ42-GFP SH-SY5Y人類神經瘤母細胞，以及動物模式APP/PS1/tau的基因轉殖鼠來進行實驗。得到的初步結果顯示，在細胞模式中NCT016可以降低乙醯膽鹼酯酶的活性；藉由降低β-secretase （β-site APP-cleaving enzyme 1，BACE1）、類澱粉前驅蛋白C端片段蛋白（APP β-C-terminal fragments，β-CTF）和類澱粉蛋白（Aβ42）的表現量以減緩類澱粉蛋白產生途徑（amyloidogenic pathway）；增加粒線體膜電位並降低Bax/Bcl-2 ratio以改善粒線體的功能；降低cleaved caspase-9 和cleaved PARP的表現量避免細胞走向細胞凋亡（apoptosis）；並且增加神經纖維（neurite）的長度和複雜度以改善神經纖維生長（neurite outgrowth）。在動物模式中，NCT016可以改善基因轉殖鼠在空間上的學習與記憶能力以及短期記憶能力；降低其大腦中類澱粉前驅蛋白（APP）、BACE1和p-tau的表現量以及減緩粒線體調控的細胞凋亡路徑。總結來說，NCT016可作為治療阿茲海默症的藥物來抑制乙醯膽鹼酯酶的活性、類澱粉蛋白產生途徑和細胞凋亡路徑，並增加粒線體功能等。
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory loss and deposition of β-amyloid (Aβ) plaques in the cortical and hippocampal region of the brain. Previous studies emphasizes that the inhibition of acetylcholinesterase (AChE) activity increases the level of acetylchline in the brain and improves cholinergic functions in AD patients. Until now, AChE inhibitors are the major class of drugs approved for AD. Thus, we identified an effective novel compound NCT016 from Scutellaria baicalensis for protecting neurons via inhibiting AChE activity by using the AD cell model of Tet-On Aβ42-GFP SH-SY5Y neuroblastoma cells in vitro, and the triple-transgenic mice (3xTg-AD) harboring PS1M146V, APPSwe, and tauP301L in vivo. Our data showed that NCT016 isolated from Scutellaria baicalensis: (1) decreased significantly the AChE activity of the AD cells, (2) attenuated the amyloidogenic pathway by decreasing the expressions of BACE1, β-CTF and Aβ aggregation, (3) increased mitochondria membrane potential and rescued mitochondrial function, (4) protected AD cells from apoptosis, (5) improved neurite outgrowth by increasing neurite length and complexity of AD cells, (6) improved AD mice performance significantly better than vehicle-treated AD mice on Morris water maze test, Y-maze test and novel object recognition task at 24th week old, and (7) attenuated the expressions of APP, BACE1, phosphorylated tau protein and mitochondria-mediated apoptosis in the cerebra of AD mice. In conclusions, NCT016 could be a potentially therapeutic compound for the treatment of AD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory loss and deposition of β-amyloid (Aβ) plaques in the cortical and hippocampal region of the brain. Previous studies emphasizes that the inhibition of acetylcholinesterase (AChE) activity increases the level of acetylchline in the brain and improves cholinergic functions in AD patients. Until now, AChE inhibitors are the major class of drugs approved for AD. Thus, we identified an effective novel compound NCT016 from Scutellaria baicalensis for protecting neurons via inhibiting AChE activity by using the AD cell model of Tet-On Aβ42-GFP SH-SY5Y neuroblastoma cells in vitro, and the triple-transgenic mice (3xTg-AD) harboring PS1M146V, APPSwe, and tauP301L in vivo. Our data showed that NCT016 isolated from Scutellaria baicalensis: (1) decreased significantly the AChE activity of the AD cells, (2) attenuated the amyloidogenic pathway by decreasing the expressions of BACE1, β-CTF and Aβ aggregation, (3) increased mitochondria membrane potential and rescued mitochondrial function, (4) protected AD cells from apoptosis, (5) improved neurite outgrowth by increasing neurite length and complexity of AD cells, (6) improved AD mice performance significantly better than vehicle-treated AD mice on Morris water maze test, Y-maze test and novel object recognition task at 24th week old, and (7) attenuated the expressions of APP, BACE1, phosphorylated tau protein and mitochondria-mediated apoptosis in the cerebra of AD mice. In conclusions, NCT016 could be a potentially therapeutic compound for the treatment of AD.
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阿茲海默症, 乙醯膽鹼酯酶, 細胞凋亡, 粒線體功能, 類澱粉蛋白產生途徑, Alzheimer’s disease, acetylcholinesterase, apoptosis, mitochondrial function, amyloidogenic pathway