| 摘要: | 腦中風後憂鬱（Poststroke depression; PSD )造成國家花費在中風有關的殘疾照護社會 成本很大一部分。腦中風後憂鬱的高死亡率，並只能輕微改善神經康復，導致更糟的運動和 認知功能，生活品質較差。中風和憂鬱症有許多共同的病理標的，尤其造成海馬迴神經再生 減少，因此產生海馬迴功能不足。越來越多的證據顯示，神經可塑性和內生性海馬迴神經再 生兩者扮演PSD病理上的關鍵作用。本研究計畫目的，我們想要利用自願運動合併使用補陽 還五湯(BHD)來促進海馬迴神經再生及相關聯作用以達到神經保護作用和抗PSD作用。特別是 以自願運動合併使用補陽還五湯治療中風後憂鬱樣行為（PSD)之小鼠模型，研究海馬迴神 經再生以及L1- INP細胞增生和可能的信號傳導途徑和所涉及神經增殖和再生的分子標靶。我 們的核心假設是自願運動合併使用補陽還五湯可以改善“興奮神經毒性”，提升“海馬迴神 經再生”，以改善中風後憂鬱（PSD )的腦缺血損傷小鼠。這一假說是基於我們的先前研 究結果顯示，經常跑步可保護小鼠減免受中風引起的腦損傷，延長小鼠的壽命與缺血性中風， 以及每日口服BHD ( 0.5-1.0克/kg)可減少腦中風自由基，發炎，血腦屏障滲漏和促進內生 性神經再生及分化，以改善腦梗塞和中風小鼠延長他們7天內的壽命。計畫研究理由是，自願 運動合併使用補陽還五湯被認為具有神經保護作用已有很長一段時間，但在小鼠缺血中風介 導的興奮性神經毒性模型探討自願運動合併使用補陽還五湯兩個簡單的方法，將可發展出有 效的中風治療策略（包括：生物標誌物和藥物靶標），以應用於缺氧/缺血相關的疾病，如中 風後憂鬱症（PSD )的治療。因此，我們的具體目標# 1 (第1年），為研究自願運動 合併使用補陽還五湯是否可以藉由調節GSK3在缺血中風小鼠模型信號增強海馬迴神經再生 和L1 - INP細胞改善中風後憂鬱（PSD)。具體目標# 2 (第二年），以研究自願運動 合併使用補陽還五湯是否可以藉由活化Notch1信號在缺血中風小鼠模型增強內生性/海馬迴 神經發生。具體目標# 3 (第3年），將利用轉錄體學(transcriptome analysis)去探討自願運 動合併使用補陽還五湯是否可以藉由激活的Wnt / /3 -catenin和Ang1/Tie2信息於缺血中風小鼠 模型增強血管生成促進血腦屏障再塑。我們的預期的結果：（1 )可以揭示自願運動合併 使用補陽還五湯的神經保護作用對缺血性中風引起的興奮性神經毒性及抗PSD作用，是否可 透過調控與GSK-3密切關聯信息或間接地干預有害信號（例如，p53和JNK/p38激酶，AP- 1) 和增強保護信號（例如，CREB ，HSF- 1 ，/3 -catenin，BDNF，PI3K/Akt，MEK / ERK) 等與GSK - 3密切相關的訊號。（2 )可以確定自願運動合併使用補陽還五湯治療是否能提 高內生性/海馬迴神經再生及遷移並促進NPC到L1-INP細胞的生成，或活化Notchl基因的參 與信息和神經生長因子（的Angl和SDF1 )表現的差異，來解釋如何透過自願運動合併使用 補陽還五湯治療可保護小鼠對抗CI/R引起的腦損傷，延長小鼠的壽命與缺血性中風。這些結 果將十分有助於支持自願運動合併使用補陽還五湯治療是缺血性腦中風及PSD的臨床治療有 益策略。（3 )可以提供證據來揭示自願運動合併使用補陽還五湯治療是否可以藉由上調 Ang1/Tie2和緊密連接蛋白（occludin)的表現，及激活的Wnt/召-catenin以增BBB重塑，降低 中風後缺血性血腦屏障滲漏(BBB leakage)，並將解釋自願運動合併使用補陽還五湯治療是否 能增加神經幹細胞遷移，藉由血管重塑，上調Ang1/Tie2或Wnt信號配體(ligand)表達，來增加 來介導此保護作用。最後，這些數據將可解釋自願運動合併使用補陽還五湯治療是否能提高 Ang1的表達，藉以促進SVZ神經幹細胞遷移。總合計畫結果將可提供該有效分子標靶，做為 臨床發展成為治療中風及PSD的藥物或策略之專一分子標靶考量。
Post-stroke depression (PSD) represents a large portion of the cost spent on the disabilities associated with stroke. Stroke patients with PSD suffer higher mortality rates and show only minor improvement in rehabilitation programs, resulting in worse functional (motor and cognitive) outcomes and poorer quality of life. Stroke and depression share common pathological substrates accessible to multitarget strategies, especially in reducing hippocampus neurogenesis and consequent deficits in hippocampal function. Increasing evidence shows that neural plasticity and endogenous hippocampal neurogenesis play key roles in both pathologies. In this current project, we intend to explore the neuroprotective and anti-PSD effects that has been associated with adult hippocampal neurogenesis by using voluntary running in combination with Chines herbal remedy Bu-yang Huan-wan Tang (BHD) treatment. Especially, hippocampal neurogenesis as well as the proliferation and neurogenesis of L1-INP cells and the possible signaling pathways or molecular targets involved after voluntary running in combination with BHD treatment in a depressive-like behavior (PSD) murine model. Our central hypothesis is that voluntary running and BHD can ameliorate “excitotoxicity” and enhance “hippocampus neurogenesis” to ameliorate post-stroke depression (PSD) in post cerebral ischemia injured mice. This hypothesis is based on our preliminary results showing that regular running protects mice against stroke-induced brain injury and extend the life span of mice with an ischemic stroke; and oral administration of BHD (0.5-1.0 g/kg) daily can reduce extraordinary amounts of free radicals, inflammation, BBB leakage and promote endogenous neurogenesis/differentiation to ameliorate brain infarction and extend their lifespan in mice with a stroke within 7 days. The rationale is that voluntary running and BHD treatment are two simple methods known to be neuroprotective for a long time and to interpret how voluntary running in combination with BHD treatment work on the ischemic stroke-mediated excitotoxicity in a murine model will lead to an effective therapeutic application (stroke biomarkers and drug targets) for hypoxia/ischemia-related disorders like post-stroke depression (PSD). Therefore, our specific aim #1 (1st year), to study whether voluntary running and BHD treatment can improve post-stroke depression (PSD) by enhancing hippocampus neurogenesis and L1-INP cells through modulating GSK3 signaling in ischemic murine model. Specific aim #2 (2nd year), to study whether voluntary running and BHD treatment can enhance endogenous/hippocampus neurogenesis through Notch1 signaling in ischemic murine model. Specific Aim #3 (3rd year), using transcriptome analysis to study whether voluntary running and BHD can promote BBB remodeling by enhancing angiogenesis through activating Wnt/p-catenin and Ang1/Tie2 signaling in ischemic murine model. Our expected results: (1) To uncover the neuroprotective effects and anti-PSD effects of voluntary running and BHD treatment (1.0-2.0 g/kg, p.o.) against ischemic stroke-induced excitotoxicity; it could be closely associated with targeting GSK-3 itself or by indirectly interfering detrimental signals (e.g., p53, JNK/p38 kinase, AP-1) and enhancing protecting signals (e.g., CREB, HSF-1, (3-catenin, BDNF, PI3K/Akt, MEK/ERK, etc) closely associated with GSK-3. (2) To identify whether voluntary running and BHD treatment can enhance endogenous/hippocampus neurogenesis, migration and differentiation of NPCs to L1-INP or and the involvement of Notch1 signaling and neural growth factors (Ang1 and Sdf1) in ischemic murine model to explain how Voluntary running and BHD treatment could protect mice against CI/R-induced brain injury and extend the life span of mice with an ischemic stroke. These results could help support voluntary running and BHD treatment to be beneficial agents for the treatment of ischemic stroke in the clinic. (3) To provide evidence to reveal whether voluntary running and BHD treatment can decreases BBB leakage through increasing vascular integrity (BBB remodeling) via up-regulating Ang1/Tie2 and tight junction protein (occludin) expression through activating Wnt/p-catenin in the ischemic brain after stroke, and will explain whether voluntary running and BHD treatment can increase neuroblast migration, which may be mediated by vascular remodeling through increasing expression of Ang1/Tie2 or Wnt ligands. Finally, these data will account whether voluntary running and BHD treatment can increase Ang1 expression, which can promote SVZ neuroblast migration. |
