臺灣博碩士論文加值系統

已知黃芩素可降低腦中風引起之發炎反應而產生神經保護作用，但其是否對於腦創傷亦有神經保護作用仍不清楚，因此我們研究給予黃芩素治療對於腦創傷大鼠的藥效，並且評估其可能的作用機制，實驗設計針對大鼠腦創傷之後行為功能的恢復、神經損害、發炎相關的細胞激素/趨化激素之表現和氧化傷害之程度進行評估。將大鼠施以可控制的皮質撞擊(速度4 m/s、深度2 mm)造成大鼠腦傷，並在創傷5分鐘之後注射黃芩素(30 mg/kg, 腹腔注射)或者溶媒；在腦創傷之後的1、4、7、14天使用跑步滾輪測試(運動)和雙側觸覺黏著移除測試(感覺/運動)評估動物神經的損害；在行為評估之後將老鼠犧牲、灌流、取腦組織進行冷凍切片；在第1和14天以甲酚紫染色測量創傷體積；在腦創傷後1天以Fluro-Jade B染色評估神經退化及自由基攻擊蛋白質及脂肪的產物(3-NT, 4-HNE)之免疫組織染色評估腦組織之氧化傷害；在創傷之後3、6小時及1、4天以懸浮式酵素聯結反應測量細胞激素和趨化激素(TNF-a, IL-1β, IL-6 & MIP-2)的蛋白質濃度；並於腦創傷後6小時以即時定量反轉錄聚合酶連鎖反應測定細胞激素和趨化激素mRNAs的表現。所有腦創傷動物皆以黏著移除及跑步滾輪等行為測試評估運動及感覺功能損害，從創傷後1天開始行為功能會隨著時間自我恢復。以跑步滾輪測試及雙側的觸覺黏著測試發現給予黃芩素治療的腦創傷大鼠在創傷之後1、4和7天行為能力相較於給予溶媒組腦創傷大鼠有明顯的改善。給予黃芩素治療也可以降低在腦創傷1天FJB退化性神經數目及在腦創傷14天的創傷體積。於腦創傷後各個時間點，腦脊髓液中前發炎細胞激素濃度皆沒有顯著增加，組織中前發炎細胞激素(TNF-a, IL-1β, IL-6)之濃度在創傷之後1天顯著上升。給予黃芩素明顯降低受傷組織中細胞激素及趨化激素(TNF-a, IL-1β, IL-6 & MIP-2)之濃度。細胞激素及趨化激素(TNF-a, IL-1β, IL-6 & MIP-2) mRNA含量顯著增加顯示有顯著的轉錄活化作用，在腦創傷之後給予黃芩素顯著降低細胞激素及趨化激素(TNF-a, IL-1β, IL-6 & MIP-2) mRNA。氧化傷害指標3-NT及4-HNE於創傷組織中細胞數目增加，給予黃芩素治療組之腦組織中3-NT及4-HNE細胞數目明顯比給予溶媒組少。這些結果表示創傷後給予黃芩素治療可降低神經損傷並且促進行為功能的恢復、降低細胞激素、趨化激素ROS攻擊產物的產量，故推論黃芩素神經保護的機制可能與抗發炎反應和減少創傷後的氧化傷害有關。

Baicalein has been shown to exert an anti-inflammatory effect following stroke insults but the protective effect in traumatic brain injury (TBI) is still unknown. We therefore examined the effect of baicalein treatment on functional recovery, neuronal damage, inflammatory cytokine/chemokine expression and markers of oxidative damage following TBI in rats. Rats with TBI caused by controlled cortical impact (CCI with 4m/s velocity, 2mm deformation) were given with baicalein (30 mg/kg, i.p.) or vehicle 5 minutes after TBI. The animals were evaluated for neurological deficits using rotarod (motor) and bilateral tactile adhesive removal tests (sensory/motor) at 1, 4, 7, 14 days after TBI. Animals were sacrified after functional evaluation by transcardial perfusion and brains were removed and sectioned by a cryostst. Brain contusion volume was measured by cresyl violet staining at 1 and 14 days. Neuronal degeneration was evaluated by Fluro-jade B (FJB) staining and markers for ROS-attacked product (3-NT, 4-HNE) were assessed by immunohistochemical staining, respectively, at 1 day. Protein concentration of cytokines and chemokines (TNF-a , IL-1β, IL-6 & MIP-2) in brain tissue and in cerebrospinal fluid (CSF) was measured by bio-plex suspension ELISA array at 3hr, 6hr, 1 day and 4 days after injury. Expression of cytokines/chemokines mRNAs was also quantitative measured by real-time reverse transcription PCR at 6 hr. All TBI animals displayed functional deficits as examined by adhesive removal and rotarod tests from day 1 after TBI and functional improvement occurred at subsequent time points. TBI rats treated with baicalein performed better on both the rotarod and bilateral tactile adhesive tests as compared with vehicle-treated animals at 1, 4 and 7 days after injury. Baicalein treatment also reduced the number FJB-positive degenerating neurons at1 day and contusion volume at 14 days. While CSF levels of pro-inflammatory cytokines did not significantly increase at each selected time point after TBI, tissue levels of pro-inflammatory cytokines (TNF-, IL-1, IL-6) were markedly elevated at 1 day after TBI. Baicalein treatment significantly reduced cytokines (TNF-, IL-1, IL-6) and chemokines (MIP-2) levels. The pro-inflammatory cytokines (TNF-, IL-1, IL-6) and chemokines (MIP-2) were all highly transcriptionally activated and revealed by the dramatical increase in their mRNA levels after TBI. Baicalein treatment significantly reduced pro-inflammatory cytokines (TNF-, IL-1, IL-6) and chemokines (MIP-2) mRNA levels. Furthermore, increased 3NT and 4-HNE immunoreactivity were detected after CCI. However, the 3-NT and 4-HNE immunoreactivity was less prominent in the baicalein-treated TBI rats than in the vehicle-treated TBI rats. These findings indicate that post-traumatic baicalein treatment reduces neuronal damage and promotes functional recovery from TBI. The reduced production of cytokines/chemokines and ROS-attacked products suggests that the neuroprotective effect of baicalein may be attributed, in part, by its anti-inflammatory and anti-oxidant mechanism(s).

頁次
目錄……………………………………………………………………………...I
中文摘要………………………………………………………………………..II
英文摘要……………………………………………………………………….IV
第一章 緒論…………………………………………………………………….1
第二章 實驗材料與研究方法………………………………………………...16
第三章 實驗結果……………………………………………………………...32
第四章 討論…………………………………………………………………...39
第五章 結論…………………………………………………………………...45
附錄…………………………………………………………………………….46
圖次…………………………………………………………………………….48
參考文獻……………………………………………………………………….80

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