中風後憂鬱(Post-stroke depression; PSD)是持續長時高風險復發的中風合併症。PSD目前 仍無法識別和治療；PSD不但使腦中風患者的死亡率提高且阻礙身體康復，更導致運動和認 知功能退化嚴重降低生活品質。腦中風和憂鬱症的共同病理標的就是海馬迴神經再生 (neurogenesis)降低，產生海馬迴功能不足；最新研究顯示神經可塑性(brain plasticity)和内生 性神經再生(neurogenesis)的減少兩者扮演PSD病理上關鍵角色，並且受特殊miRNAs的表現影 響。本研究計畫目的：擬利用自發跑步運動合併使用中風神經保護藥物『補陽還五湯(BHD)』 來促進中風鼠血管新生增加神經可塑性及神經再生以達到神經保護和抗PSD作用，並研究其 中miRNAs的表現如何調控信號傳導途徑和核心分子機制。我們的核心假設是：自發跑步運動 合併使用補陽還五湯可以透過調控miRNAs表現而影響關鍵核心分子機制以減少興奮神經毒 性，提升神經再生及神經可塑性來改善腦缺血損傷小鼠的中風後憂鬱(PSD)行為。此假說是基 於我們的先前已研究顯示：經常跑步的小鼠可保護其減少受中風引起的腦損傷，延長其壽命； 另外日口服補陽還五湯（0.5-1.0克/kg體重)可減少中風產生的巨量自由基及發炎造成的血腦 屏障破損滲漏，並促進內生性神經再生及分化，得以改善腦梗塞和延長中風鼠壽命，進一步 研究發現經常跑步合併口服補陽還五湯確實可經由抑制“興奮神經毒性”相關的CDK5及發炎 轉錄因子p65NFKB活化，進而抑制細胞凋亡（apoptosis)，並提升“海馬迴神經再生”，與活化 PI3K/Akt途徑抑制GSK3而活化p-catenin促進BDNF大量表現有關。總目標：探討自發跑步運 動合併使用補陽還五湯是否可發展成有效的中風後憂鬱症(PSD)治療策略。專一目標# 1 (第 1年）：研究自發跑步運動合併使用補陽還五湯是否可以藉由調控缺血中風小鼠特殊miRNAs 變化增強海馬迴神經再生參與改善中風後憂鬱(PSD)。專一目標# 2(第2年），自發跑步運動 合併使用補陽還五湯是否可以調控缺血中風小鼠特殊miRNAs變化增強血管新生再塑血腦屏 障及增加神經可塑性。預期的結果：可以提供證據來揭示自發跑步運動合併使用補陽還五湯 治療可以藉由改變miRNAs表現而影響關鍵基因蛋白質表現以促進血管新生，再塑血腦屏障及 增加神經可塑性與神經幹細胞；藉由分析組織/血漿中特殊miRNAs表現情形亦可做為PSD的 診斷治療分子標記。綜合計畫結果，將可提供自發跑步運動合併使用補陽還五湯，做為臨床 發展成為治療中風及PSD的新穎療法。 Stroke patients with post-stroke depression (PSD) suffer higher mortality rates and show minor improvement in rehabilitation programs, resulting in worse functional (motor and cognitive) outcomes and poorer quality of life. Decreased neurogenesis in the hippocampus and disturbance of brain plasticity are two common markers implicated in the pathogenesis of PSD, and are modulated by special miRNAs expression profiling generated by stroke. General goal: to explore the neuroprotective effect via promotion of angiogenesis and ne-^rogenesis through kev molecules regulated by special miRNA expression profiling generated bv voluntary running in combination with BHD treatment_for anti-PSD. Our central hypothesis is that voluntary running and BHD can ameliorate “excitotoxicity of stroke” and enhance “hippocampus neurogenesis，’ to 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 daily can reduce extraordinary amounts of free radicals, inflammation, B.B.B. leakage and promote endogenous neurogenesis/differentiation to ameliorate brain infarction and extend their lifespan. Performing voluntary running together with BHD treatment are neuroprotective on the ischemic stroke-mediated excitotoxicity and will lead to an effective therapeutic application for PSD. To achieve the research objective, two specific aims will be pursued: Specific Aim #1 (1st year), to study whether performing voluntary running and BHD treatment can enhance endogenous/hippocampus neurogenesis through activating key signaling/molecules modulated by specific expression profiling of miRNAs. Specific Aim #2 (2nd year), to study whether performing voluntary running and BHD can promote angiogenesis, BBB remodeling and enhancing brain plasticity through activating key signaling/molecules modulated by specific expression profiling of miRNAs. Expected Results: These data will provide evidence to identify the changed (specific) expression pattern of miRNAs and the correlation with the key signaling pathway, e.g., Wnt/GSK-3/p-catenin in mediating anti-PSD effect by performing voluntary running and BHD treatment. Identification of serum and brain tissue specifically expressed miRNAs may also serve as potential diagnostic biomarkers for PSD and to demonstrate a novel role for miRNAs in the pathogenesis of PSD as well as prognosis markers by performing voluntary running and BHD treatment.
