臺灣博碩士論文加值系統

本論文研究以使用腦中風的動物模型探討局部腦梗塞 (focal cerebral ischemia)的治療與其機轉。而研究主要的重點在針對神經滋養因子 (neurotrophic factors) 中Transforming Growth Factor-b (TGF-b)家族對於局部腦梗塞的病生理變化的影響，以供臨床治療腦中風病患的參考。
第一個研究課題在探討腦缺血後是否會產生內生性膠質細胞神經滋養因子 (Glial cell line-Derived Neurotrophic Factor; GDNF) 的表現。以往的研究顯示，由外在給予動物腦內 GDNF 可以減輕腦缺血後動物腦梗塞的大小，而 GDNF 的作用在透過與其受體 (GDNF-family receptor alpha-1 ; GFRa-1) 結合後和另一蛋白質 c-RET 所產生。 因此我們在本實驗研究中首先檢測動物腦缺血後腦中 GFRa-1 與 c-RET 的表現。
我們在麻醉動物上進行右側中大腦動脈結紮，使其支配的腦組織區域暫時缺血，90分鐘後再釋放結紮使之產生再灌流傷害 (reperfusion injury)。之後，依再灌流傷害的時間，於0、6、12 與 24 小時後犧牲動物，以 in situ hybridization 方法進行GFRa-1 與 c-RET mRNA 的測定。我們發現GFRa-1 mRNA 在腦缺血後於海馬迴的CA3區，齒狀迴(dentate gyrus；DG) 區 ，腦皮質區 (cortex) 與紋狀體區 (striatum) 都有增加的現象。在齒狀迴區中，GFRa-1 mRNA的表現於6小時後最高。在CA3區，GFRa-1 mRNA的表現為逐漸增加的趨勢。在腦皮質區中，為一直持續的表現，而在0 與24小時分別出現表現的高峰。在紋狀體區中，則是於0小時表現最高。另外，在c-RET mRNA 的表現，我們發現在紋狀體中，於0 小時就已經增加而在 6、 12、24 小時則是逐漸的增加。
綜合我們的結果發現，缺血後腦組織中GFRa-1 與 c-RET都會增加，其增加的程度受再灌流的時間之不同而表現不一。因為GDNF具有神經保護作用，在腦缺血後其受體蛋白質GFR-a1 及c-RET的表現增加，可加強GDNF的神經保護反應(responsiveness)。我們也發現在不同的腦區域中，GFRa-1及c-RET mRNA的增加也有所不同，顯示GDNF對腦中風的神經保護作用因不同的腦區域而有不同。這些結果可以說明在腦缺血後可以引發內生性GDNF的神經保護機轉。
TGF-b家族中還有另外一種主要的滋養因子，骨成形蛋白質(Bone Morphogenetic Protein，簡名BMP)。其中的BMP-6及其受體mRNA，存在於動物胚胎期與成年期的腦內。成年動物在腦受傷後，也會引發BMP-6 受體mRNA表現增加，這些現象表示BMP-6 在腦缺血後的神經保護也佔有一席之地。因此在我們第二個研究課題中，便是探討BMP-6是否在體內與體外可以提供神經保護的作用。我們發現事前給予BMP-6可以減輕H2O2對初級神經細胞培養的毒性作用；BMP-6也可以對抗H2O2減少神經細胞密度的作用。在體內的研究中，我們在動物腦缺血手術之前先給予BMP-6腦內注射 (intracerebral injection)，我們發現BMP-6並不改變腦血流量，但是卻造成腦梗塞面積的減少，並且改善動物的運動功能。利用組織細胞化學研究，我們發現BMP-6減少腦缺血後Caspase-3與TUNEL活性。這些結果顯示，BMP-6的神經保護作用可能透過抑制細胞凋亡(apoptosis)的機轉而完成。
我們在第三個研究課題中探討對於急性腦中風的另外一種治療方式：高壓氧治療(Hyperbaric Oxygenation; HBO)。在動物實行腦缺血手術後，我們分別給予：(1)立即高壓氧治療、(2)延遲高壓氧治療、(3)立即高壓空氣治療(Hyperbaric Pressure; HBP)、(4)延遲高壓空氣治療、(5)或正常壓力空氣。結果我們發現，給予正常空氣或延遲高壓空氣治療對腦中風沒有治療效果。在給予延遲高壓空氣治療後，雖然使動物神經功能有恢復的趨勢，但是並不能有效減少腦梗塞的大小。反觀，給予立即高壓氧治療或腦缺血 後60分鐘給予高壓氧治療，卻可以有效減少腦梗塞的大小，並且使動物的神經功能測試得以進步。此研究進一步提供我們另一項可以立即使用在臨床急性腦中風病患的輔助治療方式。
以往的研究顯示，甲基安非他命(Methamphetamine; MA)與腦缺血都可以使過氧化物(reactive oxygen species)的生成增加，進而活化細胞凋亡的途徑而使腦傷害增加。本論文的最後一個研究重點，在探討神經滋養因子GDNF、腦缺血傷害、甲基安非他命、與細胞凋亡之間的關係。我們發現動物在腦缺血手術前給予甲基安非他命會增加腦中的嚴重度。分別給予動物甲基安非他命或只有腦缺血手術，都使腦中細胞凋亡前分子(pro-apoptotic molecule) p53的mRNA增加，而且甲基安非他命對腦缺血增加p53 mRNA的程度有加成的作用。另外，給予甲基安非他命使腦中GDNF含量減少，而事前給予動物GDNF可以對抗甲基安非他命對腦缺血傷害的加成作用。綜合這個研究課題的結果，甲基安非他命可能透過降低內生性GDNF的神經保護作用，及增加細胞凋亡的機轉，因而加強了腦缺血的傷害。
總結，由本論文的研究結果，我們可以得知細胞凋亡在缺血後的腦損傷延伸中扮演一項重要角色。也說明了內生性GDNF為提供腦缺血後神經保護的作用機轉。我們的研究結果更進一步說明了，TGF-b家族的神經滋養因子，在急性腦中風預防與治療上的角色。

This dissertation research focused on focal cerebral ischemia, using the middle cerebral artery occlusion model in rats and mice. Studies were conducted primarily to examine influences of TGF-β family trophic factors on the sequalae of pathophysiological events.
One study examined changes in the receptor for GDNF to test the hypothesis of an endogenous GDNF neuroprotective system.(Time Course Study of GFRa-1 Expression in an Animal Model of Stroke. Sarabi A, Chang CF, Wang Y, Hoffer BJ, and Morales M. Exp Neurol. 2001;170:283-289.) Previous studies have shown that intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) reduces ischemia-mediated cerebral infarction. The biological effects of GDNF are mediated by GDNF-family receptor alpha-1 (GFRa-1) and c-Ret. In this study, we examined the levels of expression of GFRa-1 and c-Ret in a rat model of stroke. Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The right middle cerebral artery was ligated at its distal branch for 90 min. Animals were sacrificed at 0, 6, 12, and 24 h after reperfusion and levels of expression of GFRa-1 and c-Ret mRNA were determined by in situ hybridization histochemistry. We found that GFRa-1 mRNA was up-regulated in CA3, dentate gyrus (DG), cortex, and striatum. The peak of up-regulation in DG was 6 h after reperfusion. GFRa-1 mRNA levels in CA3 were gradually up-regulated over the 24-h reperfusion period. In cortex, GFRa-1 mRNA was up-regulated at all time points; however, the peak of up-regulation was observed at 0 and 24 h after reperfusion. In striatum, an initial up-regulation of GFRa-1 was found at 0 h after ischemia. In striatum, up-regulation of c-Ret mRNA was detected as early as 0 h after reperfusion. A gradual increase was found at 6, 12, and 24 h after reperfusion. In conclusion, our results indicate that there are both regional and temporal differences in up-regulation of GFRa-1 and c-Ret after ischemia. Since GDNF is neuroprotective, up-regulation of GFRa-1 and c-Ret could enhance the responsiveness to GDNF and reduce neuronal damage. The selective up-regulation of GFRa-1 and c-Ret in different brain areas suggests that there may be regional differences in GDNF-induced neuroprotection in stroke. These changes in receptors for GDNF supports the hypothesis of an endogenous GDNF neuroprotective mechanism and extends earlier data showing a parallel upregulation of GDNF itself in stroke.
A second study investigated another member of the TGF-β family, termed Bone Morphogenic Protein-6 (BMP-6) in this same rat model of focal ischemia. (Bone Morphogenetic Protein-6 Reduces Ischemia-Induced Brain Damage in Rats. Wang Y, Chang CF, Morales M, Chou J, Chen H-L, Chiang Y-H, Lin S-Z, Cadet J L, Deng X, Wang, J-Y, Chen, S-Y , Kaplan PL, and Hoffer,BJ. Stroke. 2001;32:2170-2178.) Bone morphogenetic protein-6 (BMP-6) and its receptors are expressed in adult and fetal brain.Receptors for BMP-6 are upregulated in adult brain after injury, leading to the suggestion that BMP-6 is involved in the physiological response to neuronal injury. The purpose of my study was to determine whether there was a neuroprotective effect of BMP-6 in vivo and in vitro. Lactate dehydrogenase and microtubule-associated protein-2 (MAP-2) activities were used to determine the protective effect of BMP-6 against H2O2 in primary cortical cultures. The neuroprotective effects of BMP-6 were also studied in chloral hydrate—anesthetized rats. BMP-6 or vehicle was injected into right cerebral cortex before transient right middle cerebral artery (MCA) ligation. Animals were killed for triphenyl-tetrazolium chloride staining, caspase-3 immunoreactivity and enzymatic assays, and TUNEL assay. A subgroup of animals were used for locomotor behavioral assays.
Application of H2O2 increased lactate dehydrogenase activity and decreased the density of MAP-2 neurons in culture. Both responses were attenuated by BMP-6 pretreatment. Complementary in vivo studies showed that pretreatment with BMP-6 increased motor performance and generated less cerebral infarction induced by MCA ligation/reperfusion in rats. Pretreatment with BMP-6 did not alter cerebral blood flow or physiological parameters. There was decreased ischemia-induced caspase-3 immunoreactivity, caspase-3 enzymatic activity, and density of TUNEL-positive cells in ischemic cortex in BMP6-treated animals. BMP-6 thus reduces ischemia/reperfusion injury, perhaps by attenuating molecular events underlying apoptosis. Because GDNF and BMP-6 utilize entirely different receptors and intracellular second messengers, these experiments also suggest a “cocktail” of trophic factors may provide optimal neuroprotection in stroke.
A third study examined another approach to provide neuroprotection for cerebral ischemia, utilizing hyperbaric oxygen. (Hyperbaric oxygen therapy for treatment of postischemic stroke in adult rats. Chang CF, Niu KC, Hoffer BJ, Wang Y, and Borlongan CV. Exp Neurol. 2000;166:298-306.) The hypothesized efficacy of hyperbaric oxygen (HBO) therapy for treatment of stroke was tested in this study. Adult rats were subjected to occlusion of the middle cerebral artery and subsequently exposed to HBO (3 atm, 2 x 90 min at a 24-h intervals. Animals terminated shortly after the second HBO treatment) or hyperbaric pressure (HBP; 3 atm, 2 x 90 min at a 24-h interval; animals terminated shortly after the second treatment) immediately after the ischemia or after a 60-min delay generally displayed recovery from motor deficits at 2.5 and 24 h of reperfusion. There was also a reduction in cerebral infarction at 24 h of reperfusion compared to ischemic animals subjected to normal atmospheric pressure. While both HBO and HBP treatments promoted beneficial effects, HBO produced more consistent protection than HBP. Treatment with HBO immediately or 60 min after reperfusion produced equally significant attenuations of both cerebral infarction and motor deficits. In contrast, protective effects of HBP treatment against ischemia were noted only when administered immediately after ischemia; there was a significantly reduced infarction volume, but only a trend toward decreased behavioral deficits. The present results demonstrate that HBO and, to some extent HBP, reduce ischemic brain damage and behavioral dysfunctions. Thus, we have validated the use of HBO in clinical situations after acute stroke.
The last study in this thesis examined the mechanisms of methamphetamine facilitation of ischemic cerebral injury. (Methamphetamine potentiates ischemia/reperfusion insults after transient middle cerebral artery ligation.Wang Y, Hayashi T, Chang CF, Chiang YH, Tsao LI, Su TP, Borlongan C, and Lin SZ. Stroke. 2001;32:775-82.) Previous studies have indicated that both methamphetamine (MA) and ischemia/reperfusion injuries involve reactive oxygen species formation and activation of apoptotic mechanisms. That MA could have a synergistic or additive effect with stroke-induced brain damage is possible. The purpose of the present study was to investigate whether administration of MA in vivo would potentiate ischemic brain injury. Adult CD-1 mice were pretreated with MA or saline. Each animal was later anesthetized with chloral hydrate and placed in a stereotaxic frame. A subset of animals received intracerebral administration of GDNF. The right middle cerebral artery and bilateral carotids were transiently occluded for 45 minutes. Regional cerebral blood flow was measured by laser Doppler. Animals were sacrificed for triphenyltetrazolium chloride staining and p53 mRNA Northern blot assay after 24 hours of reperfusion. Cortical and striatal GDNF levels were assayed by ELISA.
We found that pretreatment with MA increased ischemia-induced cerebral infarction. Ischemia or MA alone enhanced p53 (a pro-apoptotic molecule) mRNA expression. Moreover, MA potentiated expression of p53 mRNA in the ischemic mouse brain. MA pretreatment decreased GDNF levels in ischemic striatum. Intracerebral administration of GDNF before ischemia reduced MA-facilitated infarction. Our data indicate that MA exacerbates ischemic insults in brain, perhaps through the inhibition of GDNF-mediated pathways and suggest that MA may antagonize endogenous neuroprotective pathways as part of its mechanism of action. In addition, MA may also upregulate pro-apoptotic mechanisms, contributing to the ultimate extent of infarction.
Taken together, these studies strengthen the hypothesis that apoptotic mechanisms are important in determining the extent of infarction after focal cerebral ischemia. They further provide a preclinical basis for exploring new potential therapies based on trophic proteins, particularly in the TGF-β family.

頁次
目 錄……………………………… I
表次目錄……………………………… II
圖次目錄...……………………………. III
附錄目錄……………………………… V
中文摘要……………………………… VI
英文摘要..……………………………... X
第一章 緒言…………………………. 1
第二章 材料與方法…………………. 9
第三章 結果………………………… 19
第四章 討論………………………… 28
第五章 結論………………………… 35
第六章 參考文獻…………………… 63
附錄…………………………………... 76

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