摘 要
中風是一種具潛在致命的腦血管疾病，因此有許多研究都致力於中風的治療。最近的研究指出，sphingosine-1-phosphate (S1P) agonist能顯著降低缺血性中風所造成的腦受傷體積。然而，對於與S1P同屬於溶血磷脂質 (lysophospholipids, LPLs)的lysophosphatidic acid (LPA)，其對中風的治療效應，目前並無相關的討論。
本研究以大白鼠為實驗動物，探討LPA 1/3受器的agonist VPC31143 (VPC)是否對永久性中大腦動脈梗塞 (permanent middle cerebral artery occlusion, PMCAO)大白鼠腦組織具有神經保護的作用。我們首先建立一套大白鼠中大腦動脈梗塞的腦中風動物模式，然後將接受PMCAO手術的雄性大白鼠分成control、vehicle、high-dose VPC、及low-dose VPC四組。此四組大白鼠於手術30分鐘後，分別接受無處理、腹腔注射3%幼牛血清白蛋白(bovine serum albumin, BSA; 1mL/kg)、腹腔注射0.8 mg/kg/mL VPC、與腹腔注射0.25 mg/kg/mL VPC的處理。我們並於大白鼠中風24小時後，紀錄各組的存活率。以Garcia Score評量表評估各組大白鼠大腦的感覺與運動功能，並測量與計算各組大白鼠腦的中風腦體積，與中風體積對全腦體積比例。所得結果以統計方法分析各組間的死亡率、體感覺(somatosensory)與運動功能、及大腦中風體積比率的差異。
實驗結果分析顯示，VPC可顯著減少PMCAO大白鼠於中風24小時後的死亡率、減少中風後感覺與運動的缺損程度、並降低中風體積比例。此結果突顯LPA在中樞神經系統受損時之保護效應。而此保護機制可能是經由LPA受器所耦合的PI3K訊息傳遞路徑所達成。此假設的正確性，則有待日後於轉錄與轉譯階層的確認。

Abstract
Stroke is a potentially lethal cerebrovascular event. Many research studies devoted to the treatment of stroke. In a recent study, sphingosine-1-phosphate (S1P) has the function of reducing the brain infarct volume. However, no study has yet demonstrated that lysophosphatidic acid (LPA) has this function. LPA and S1P are thought to be the two functionally important LPLs with high structural similarity. Although the neuroprotective function of S1P in TIA rat was confirmed, the effects of LPA on the brain damage after ischemic stroke of animal remain unclear.
In this study we evaluated the neuroprotective effects of LPA1/3 receptor agonist (VPC31143; VPC) on rat brains subjecting to permanent middle cerebral artery occlusion (PMCAO). A reliable surgical model of rat PMCAO was first established. Thereafter, the animals were divided into control, vehicle, high-dose VPC, and low-dose VPC groups. The vehicle group received intraperitoneal (i.p.) injection of 3% bovine serum albumin (BSA; 1 ml/kg) 30 minutes after PMCAO surgery. The high-dose VPC and the low-dose VPC group respectively received 0.8 mg/kg and 0.25 mg/kg of i.p. injection of VPC (in 3% BSA) 30 minutes after PMCAO surgery. The mortality rate, infarct volume ratio, and the neurobehavioral outcome were measured 24 hours after PMCAO and statistically analyzed for the difference between treatments.
Analyses of the experimental results showed that VPC treatment significantly reduced the mortality rate and the infarct volume ratio of the rats 24 hours after PMCAO. The neurobehavioral scores also showed the improved outcome in stroke rats treated with VPC. The beneficial effect of VPC to the ischemic brain was thought to be mediated through the PI3K signal transduction pathway. Further studies at the transcriptional and the translational levels will further confirm this postulation.

目 錄
審定書…………………………………………………………………………… 2

中文摘要………………………………………………………………………… 3

英文摘要………………………………………………………………………… 4

前言……………………………………………………………………………… 5

材料與方法……………………………………………………………………… 10

結果與討論……………………………………………………………………… 19

結論……………………………………………………………………………… 27

參考文獻………………………………………………………………………… 28

表格……………………………………………………………………………… 33

圖形……………………………………………………………………………… 38

附錄……………………………………………………………………………… 42

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