臺灣博碩士論文加值系統

根據中醫理論腦中風發生的主要原因是由於血瘀，而紅花自古以來被認為具有活血化瘀的作用。現代研究已說明紅花有抗氧化、抗發炎以及抑制glutamate所仲介的損傷，對神經細胞有保護作用等。因此本實驗的目的是探討紅花對腦梗塞的效用，以及對氧化自由基、TNF-α、IL-1β和血糖的關係。總共有72隻雄性Spragrue-Dawley (SD)大鼠被研究。實驗一（54隻）我們阻斷兩側的總頸動脈和右中腦動脈腦血流90分鐘，然後再灌流24小時，建立一個缺血─再灌流腦損傷腦梗塞大鼠之動物模型，於腦血流阻斷前分別投予0.2 g/kg、0.4 g/kg、0.6 g/kg的紅花和MK801 1 mg/Kg，以及阻斷後30 分鐘和再灌流2小時分別投予0.4 g/kg的紅花。以腦梗塞面積的比率和神經狀態做為指標來評估紅花對腦梗塞的效用，整個實驗過程也測量直腸溫度。實驗二（18隻），於腦血流阻斷前，阻斷後90分鐘和再灌流2小時分別測量股動脈血中的lucigenin-chemiluminescence (CL) counts，以及再灌流24小時後，觀察腦梗塞區域TNF-α、IL-1β染色陽性細胞的變化。結果顯示紅花0.2 g/kg、0.4 g/kg、0.6 g/kg和MK801前治療，以及0.4 g/kg在梗塞後30分鐘後治療都能減少大鼠的腦梗塞面積。又紅花0.4 g/kg、0.6 g/kg和MK801前治療也能減少神經學缺損。另外，紅花0.4 g/Kg能減少再灌流2小時的lucigenin-CL counts，以及TNF-α和IL-1β染色陽性細胞，但紅花對直腸溫度和血糖則沒有影響。
結論是紅花能減少缺血─再灌流損傷腦梗塞大鼠的腦梗塞面積和神經缺損，推測紅花能用來治療人類腦梗塞的急性期。紅花對腦梗塞的效用與它能抑制超氧陰離子減少氧化自由基的產生、以及減少TNF-α和IL-1β抑制發炎反應有關，但與直腸溫度和血糖沒有關係。
關鍵詞：紅花、缺血─再灌流、腦梗塞、神經缺損、超氧陰離子、TNF-α染色陽性細胞、IL-1β染色陽性細胞

According to the theory of Traditional Chinese medicine, cerebrovascular accident mainly results from blood stasis. Carthamus tinctorious L. (CT) is considered that has the action of activate blood to eliminate stasis since long time ago. Several studies have known recently that CT has antioxidant, ant inflammation and inhibiting glutamate-mediated injury action, and also can protect neuronal cell in the brain. Therefore, the purpose of the present study is to investigate effect of CT on cerebral infarct. A total of 72 male Sprague-Dawley (SD) rats were studied. In experiment one (54 SD), an animal model of cerebral infarct was established by occluding bilateral common carotid arteries (CA) and the right middle cerebral artery (MCA) for 90 min, then reperfusion for 24 hrs. Intra- peritoneal (ip) administration of CT 0.2 g/kg, 0.4 g/kg, 0.6 g/kg and MK801 1.0 mg/kg 10 min before , and CT 0.4 g/kg 30 min after occluding the cerebral blood flow, respectively. In addition, CT 0.4 g/kg i.p. was done 30 min after reperfusion of 2 hrs. The cerebral infarct size and grade of neurological deficit were used as an index to evaluate the effect of CT on cerebral infarct. The superoxide anion was measured by lucigenin- Chemiluminescence (CL) counts before and 90 min after occluding the cerebral blood flow, and 2 hrs after reperfusion, respectively. The tumor necrosis factor-alfa (TNF-α) and interleukin-1beta (IL-1β) immunostaining in the core of cerebral infarct area, and the levels of blood sugar were also measured 24 hrs after reperfusion. The results indicated that pretreatment with CT 0.2 g/kg, 0.4 g/kg, 0.6 g/kg, MK801, and post-treatment with CT 0.4 g/kg all decreased the ratio of cerebral infarct area. Pretreatment with CT 0.4 g/kg or 0.6 g/kg also decreased the grade of neurological deficit. Pretreatment with CT 0.4 g/kg can decrease the lucigenin-CL counts at reperfusion of 2hrs, and it also can decreased the counts of both TNF-α and IL-1β immunostaining positive cells in the cerebral infarct area, but the levels of blood sugar and rectal temperature were similar to the control.
In conclusion, CT can decrease both the ratio of cerebral infarct area and grade of neurological deficit, suggesting can be used to treat acute stage of cerebral infarct in humans. This effect of CT has relationship to inhibit superoxide anion to reduce the generation of oxygen free radicals, and decreased proinflammatory cytokine TNF-a and IL-1β resulting to inhibit inflammatory response, but no relationship to blood sugar and rectal temperature were noted.
Keywords: Carthamus tinctorious L., Cerebral infarct, Neurological deficit, Superoxide anion, TNF-α、IL-1β

第一章 前言 1
1-1.缺血性中風的流行病學、病理生理 1
1-2.缺血性中風的治療概況、研究方向及瓶頸 1
1-3.缺血性中風發生後腦組織的分生變化 2
1-4.發炎前驅細胞激素(proinflammation cytokines)與缺血性
中風的關係 3
1-5.中醫應用活血化瘀中藥的源流 3
1-6.活血化瘀藥對缺血─再灌流損傷腦梗塞之研究 4
1-7.本研究之目的........................................................................................................................... 4
第二章 文獻探討 6
2-1.中醫治療中風之理論源流 6
2-2.紅花之文獻探討 8
2-3.紅花之現代藥理研究 11
2-4.研究缺血性中風的動物模型 13
2-5.缺血性腦梗塞後之神經細胞毒性物質之產生及傷害 14
2-6.缺血性腦梗塞後自由基的產生和傷害 17
2-7.缺血性腦梗塞後的發炎反應 19
2-8.非鈣離子依賴性NMDA受體阻斷劑-MK801之研究 25
第三章 材料與方法 27
3-1.動物 27
3-2.動物模型之建立 27
3-3.藥物製備、給藥劑量、給藥方式 29
3-4.實驗分組及流程 30
3-5.生理、生化指標之測定 33
3-6.神經學狀態評估 34
3-7.腦梗塞面積之測量 36
3-8.超氧陰離子(superoxide anion; O2-)之測定 37
3-9.免疫組織化學染色 39
3-10.統計分析 40
第四章 結果 41
4-1.缺血-再灌流損傷大鼠腦梗塞動物模型 41
4-2.紅花對缺血-再灌流損傷腦梗塞大鼠的效用 41
4-3.紅花對缺血-再灌流損傷腦梗塞大鼠神經學缺損的效用 41
4-4.紅花對缺血─再灌流損傷大鼠的生理生化效用 42
4-5.紅花對缺血-再灌流損傷腦梗塞大鼠超氧陰離子之效用 43
4-6.紅花對缺血-再灌流損傷腦梗塞大鼠腦梗塞區域TNF-α
染色陽性細胞之效用 44
4-7.紅花對缺血-再灌流損傷腦梗塞大鼠梗塞區域IL-1β
染色陽性細胞之效用 44
第五章 討論 59
5-1.本研究的設計是正確，而且結果值得信賴 59
5-2.紅花可以減少缺血─再灌流損傷腦梗塞大鼠的腦梗塞面積 59
5-3.紅花能改善缺血─再灌流損傷腦梗塞大鼠的神經學狀態 60
5-4.紅花減少缺血─再灌流損傷腦梗塞大鼠的腦梗塞面積
可能與氧化自由基有關 60
5-5.紅花能減少缺血─再灌流損傷腦梗塞大鼠的發炎前驅細胞
激素(pro-inflammation cytokine)─TNF-α染色陽性細胞 61
5-6.紅花能減少缺血─再灌流損傷腦梗塞大鼠發炎前驅細胞
激素(pro-inflammation cytokine)─IL-1β染色陽性細胞 62
5-7.紅花不會影響缺血─再灌流損傷腦梗塞大鼠的生理功能 62
5-8.紅花不會影響缺血─再灌流損傷腦梗塞大鼠的肝、腎功能、周
邊血液和血糖 63
第六章 結論 64
第七章 參考文獻 65
英文摘要 75
圖目錄
圖2.1 缺血性中風後事件 16
圖3.1 實驗一流程 31
圖3.2 實驗二流程 32
圖3.3 神經學狀態評估 35
圖3.4 取腦、切片、染色、照相存檔 37
圖3.5 微量化學發光儀測量法 38
圖4.1 腦冠切片圖 45
圖4.2 梗塞面積比率評估 46
圖4.3 神經學缺陷級數評估 47
圖4.4 體重喪失評估 48
圖4.5 超氧陰離子之測量 49
圖4.6 TNF-α免疫染色陽性細胞計數測量 50
圖4.7 IL-1β免疫染色陽性細胞計數測量 51
圖4.8 TNF-α、IL-1β之計算面積位置標示圖 52
圖4.9 TNF-α、IL-1β之免疫組織化學分析 53
表目錄
表2.1 缺血後大腦的氧化內生性酵素....................................................19
表4.1 直腸溫度變化表.............................................................................54
表4.2 平均動脈壓變化表..........................................................................55
表4.3 心跳速率變化表...............................................................................56
表4.4 周邊血球指標變化表.......................................................................57
表4.5 肝腎功能、血糖測量表....................................................................58

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