2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643599摘要：阿茲海默症是目前最常見的失智症。隨著人口老化問題，在台灣阿茲海默症盛行率也隨之倍增， 衍生而來的醫療與經濟問題將愈加嚴重。目前治療阿茲海默症的藥物主要為膽鹼酶 (acetylcholinesterase; AChE)抑制劑如：愛憶欣（Aricept，donepezil)、憶思能 (Exelon，rivastigmine)、利憶靈（Reminyl, galantamine)，健保給付規定限輕度至中度之失智症； 以及目前已核准上市的NMDA接受體拮抗劑memantine (Witgen威智與Ebixa憶必佳），則核准使用 於治療中重度及重度阿茲海默症患者，然而這些藥物的療效有限，且有嚴重的副作用。因此極需發展 治療阿茲海默症之新標的藥物。我們之前的研究結果顯示RGN可以藉由活化NO-cGMP-PKG這條訊息傳遞路徑，顯著的促進神經可塑 性的表現，以及學習記憶的促進作用。我們最近利用阿茲海默症雙基因選殖老鼠（APP/PS1 mice)， 發現APP/PS1老鼠在十二個月左右，不論是莫式水迷津或T型迷津（T-maze)的學習記憶能力比起 wild-type小鼠均有明顯地缺失，但是在學習前給予RGN則可以有效改善其認知障礙。顯示RGN在治 療阿滋海默症的記憶缺失，具有良好的發展潛力，然而RGN具有首渡效應（first-pass metabolic effect)，因此我們之後又經由實驗篩選RGN之其他衍生物，目前已發展出具有效過頗佳的新穎化合 物。初步實驗顯示NO-cGMP促進劑具有改善阿茲海默症老鼠的記憶認知功能與神經保護之效果。 綜合以上結果，我們將在兩年内完成下列目標(1)我們已和成功大學洪欣儀助理教授合作，取得二十多個新的衍生化合物，我們將使用cyclicGMP EIA kit在SH-SY5Y神經培養中給予NO-donor+ phosphodiesterase抑制劑快速篩選出具有生物活性之 結構藥物，快速的建立構效(SAR)關係，並找出較具發展潛力之化合物。(2)將利用初代海馬迴或大腦皮質神經細胞培養篩選有效對抗Ap神經毒性之神經保護劑。(3)將利用大鼠侧腦室給予Ap所引起之恐懼記憶學習障礙之動物模式，篩選有效之藥物標的。(4)將利用年輕的B6小鼠（八週大)及年老的阿茲海默症雙基因選殖鼠（12個月），確認急性投藥對於水 迷宮，T型迷宮及恐懼記憶學習之促進效果。(5)將進一步探討該系列衍生物慢性投予兩個月後，對於APP/PS1阿茲海默症雙基因選殖鼠的神經退 化使否有減緩效果，及探討其作用機轉。本計晝將可開發一系列新的衍生化合物，且具有治療阿茲海默症或失智症的潛力，申請新的物質 專利。<br> Abstract: Alzheimer’s disease (AD) is the most common form of dementia. The incidence of the AD is rising inline with the aging population. Mild cognitive impairment (MCI) is a disorder that has been associated withrisk for Alzheimer's disease. Current treatment focuses on enhancing cholinergic signaling, such asacetylcholinesterase inhibitors (e.g. rivastigmine and donepezil) or decreasing glutamatergic excitotoxicitythrough antagonism of the N-methyl-d-aspartate (NMDA)-receptor (e.g. memantine). However, the efficacyof these drugs is limited and some induce serious side effects. On the other hand, the cognition enhancementis limited. Therefore, it is urgent to find new targets for developing drugs to treat AD/MCI patients.We have previously found a compound of RGN, which potentiates nitric oxide-soluble guanylylcyclase-PKG to enhance the synaptic plasticity and improve the learning behavior in rodents. Recently, wefound that 12-month-old APP/PS1 mutant mice (the animal model for AD) display memory deficits nomatter in Morris water maze or T-maze tasks in comparison with wild-type mice. However, acute treatmentof RGN effectively improved the memory function in old APP/PS1 mutant mice. Furthermore, chronictreatment with RGN for two months inhibits neurodegeneration in old APP/PS1 mice. Incubation with RGNinhibits β-amyloid (Aβ)-induced neurotoxicity in primary hippocampal neuronal cultures. These resultssuggest that RGN is promising to be developed for the treatment of AD. Since the RGN has first-passmetabolic effect, we then screened more new compounds and found more effective derivatives.We will examine the following items within two years.(1) We will measure the effects of these compounds on the cGMP content in the presence of NO-donorsodium nitroprusside and PDE inhibitor IBMX in neuronal cultures by using cyclic GMP EIA kit. Thecorrelation of learning behavior to cGMP formation can be compared from these data.(2) We will examine the neuroprotective actions of these compounds against Aβ-induced neuron toxicity inSH-SY5Y, primary hippocampal or cortical neuronal cultures.(3) We will examine the neuroprotective actions of these compounds against intracerebroventricular injectedAβ-induced impairment of fear memory and spatial learning behavior.(4) We will examine the learning and memory enhancement of these compounds in both young normal B6mice (8 weeks-old, easier for test) and aged (12 month-old) APP/PS1 mutant mouse model of AD usingMorris water maze, T-maze and passive avoidance tests.(5) We will further investigate the neuroprotective actions of chronic treatment of these compounds (for twomonths) in 10-month-old APP/PS1 mice. The related neuroprotection mechanism will also be explored.From this project, a new category of drug will be developed for the treatment of AD/ MCI.