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研究生:張麗嫣
研究生(外文):Li-yen Chong
論文名稱:透過激活過氧化體增生活化受體-gamma可保護幼鼠腦部白質傷害
論文名稱(外文):Activation of Peroxisome Proliferator-Activated Receptor-gamma Protects against White Matter Injury in Immature Mice Brain
指導教授:黃朝慶黃朝慶引用關係
指導教授(外文):Chao-Ching Huang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:80
中文關鍵詞:白質傷害大腦周腦室白質軟化症幼鼠過氧化體增生活化受體-gamma
外文關鍵詞:periventricular leukomalaciawhite matter injuryperoxisome proliferator activated receptor-gammarosiglitazonePPAR-gammaneonatal brain
相關次數:
  • 被引用被引用:0
  • 點閱點閱:119
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  • 下載下載:10
  • 收藏至我的研究室書目清單書目收藏:0
目前統計顯示,早產兒約有25%的機會罹患腦性麻痺以及認知缺陷的疾病。在臨床上,導致早產兒雙下肢腦性麻痺的神經性疾病稱作大腦周腦室白質軟化症,主要是由大腦深部白質受損所引起的腦傷。大腦周腦室白質軟化症的主要成因包括:血管發育不全/受損;發炎反應上升以及細胞凋零加劇。目前在成鼠的動物實驗結果中證實,過氧化體增生活化受體-gamma扮演的角色不僅是醣類及脂肪代謝中重要的調節因子,透過促進劑激活過氧化體增生活化受體-gamma還能有效的降低成鼠腦部的神經退化以及發炎反應。因此,我們假設在幼鼠中,過氧化體增生活化受體-gamma的激活能夠保護腦部白質傷害;相反的,利用過氧化體增生活化受體-gamma基因缺失老鼠則會看見更嚴重的白質傷害。
首先,我們建立了一個缺氧窒息腦傷的老鼠疾病模式。在缺氧後第七天,與對照組(25% 二甲基亞楓,DMSO)相比之下,我們發現於缺氧前90分鐘給予幼鼠注射過氧化體增生活化受體-gamma促進劑,rosiglitazone (3 mg/kg 溶於 25% DMSO),將能顯著的降低周腦室白質以及海馬迴的受傷(P<0.05)。於缺氧後24小時切片觀察,我們也發現原本由缺氧窒息導致的血腦屏障受損、小膠質細胞活化、甲型腫瘤壞死因子表現以及細胞凋亡現象,在rosiglitazone治療組相較於對照組皆有顯著的改善。我們進一步利用過氧化體增生活化受體-gamma的基因缺失鼠--PpargP465L/+老鼠進行同樣的實驗,以探討過氧化體增生活化受體-gamma在幼鼠白質傷害中的角色。在缺氧後第七天,PpargP465L/+ 相較於野生型老鼠有更嚴重的白質傷害 (P<0.05)。此外,缺氧窒息導致的血腦屏障受損、小膠質細胞活化、甲型腫瘤壞死因子表現以及細胞凋亡現象,在PpargP465L/+組中皆較野生型老鼠更顯著的提高。總結我們的研究成果,我們發現過氧化體增生活化受體-gamma的激活可保護幼鼠白質傷害,其保護機轉包括血管保護、抗發炎以及抗凋亡。反之,過氧化體增生活化受體-gamma基因缺失則會加重血管受傷、發炎反應以及細胞凋亡。因此,我們認為過氧化體增生活化受體-gamma在幼鼠白質傷害中扮演非常重要的角色。我們的實驗結果更加証明了過氧化體增生活化受體-gamma促進劑具有作為臨床上治療小兒白質受傷藥物的前瞻性。
Up to 25% of preterm survivors have cerebral palsy and cognitive deficits. The underlying pathology for cerebral palsy in the premature infants is periventricular leukomalacia (PVL), a developmental lesion of the deep cerebral white matter. Vascular immaturity, inflammation and apoptosis are major pathogenesis factors of PVL. Animal experiments have shown that activation of peroxisome proliferator activated receptor (PPAR)-gamma, a key regulator of glucose and fat metabolism, effectively attenuated neurodegenerative and the inflammatory processes in adult brain. Thus, we hypothesized that activation of PPAR-gamma protects against white matter injury (WMI), on the contrary, PPAR-gamma gene deficiency exacerbates WMI in neonatal brain.
We found that pre-treatment with a PPAR-gamma agonist, rosiglitazone (3 mg/kg in 25% of DMSO), significantly attenuated hypoxic ischemia injury in the white matter and hippocampus (P<0.05). The rosiglitazone-mediated protection in the white matter was associated with attenuation of activated microglia, TNF-alpha expression, extravasation of IgG and activated caspase-3 (+) cells after hypoxic ischemia. PpargP465L/+ mice, which harbor an allele with dominant negative mutant in PPAR-gamma, showed exacerbated WMI than wild-type pups (P<0.05). Moreover, HI-induced microglia activation and upregulation of TNF-alpha, extravasation of IgG and activated caspase-3 (+) cells were enhanced in PpargP465L/+ mice than in wild-type pups 24 hours after hypoxic ischemia. In summary, activation of PPAR-gamma protects against WMI, while PPAR-gamma deficiency worsens WMI by enhancing neuroinflammation, blood-brain barrier damage and cell apoptosis after hypoxic ischemia. These findings suggest that PPAR-gamma agonists are attractive therapeutic targets for treating WMI in neonatal brain.
ABSTRACT...................................................1
中 文 摘 要................................................3
ACKNOWLEDGEMENTS...........................................5
CONTENTS...................................................7
TABLE.....................................................10
FIGURE....................................................11
ABBREVIATION INDEX........................................13
INTRODUCTION..............................................14
White matter injury in neonatal brain.....................14
The pathogenesis factors of white matter injury in neonatal brain.....................................................16
Blood-brain barrier damage................................16
Inflammation..............................................16
Apoptosis.................................................19
Activation of peroxisome proliferator-activated receptor-g.........................................................19
Propose of our study......................................22
MATERIALS AND METHODS.....................................23
Animals...................................................23
Hypoxic-ischemic white matter injury in P10 mice..........23
Drug administration.......................................24
Genotyping: DNA preparation and PCR.......................24
Pathological assessment...................................25
Grey matter damage........................................26
White matter damage.......................................26
Neuroinflammation: microglia/macrophage activation and TNF-a expression..............................................27
Blood-brain barrier permeability determined by IgG leakage...................................................28
Apoptosis marker..........................................29
Tissue RNA extraction.....................................30
Reverse transcription and Real-time PCR...................30
Data analysis.............................................31
RESULTS...................................................32
A hypoxic-ischemic white matter injury model in mouse pups......................................................32
Rosiglitazone, a PPAR- g agonist, effectively attenuated brain injury..............................................33
Rosiglitazone attenuated microglia/macrophage activation in the white matter after hypoxic ischemia...................33
Rosiglitazone reduced TNF-a �nup-regulation in the white matter after hypoxic ischemia.............................34
Rosiglitazone reduced blood-brain barrier permeability in the white matter after hypoxic ischemia...................34
Rosiglitazone reduced cell apoptosis in the white matter after hypoxic ischemia....................................35
PPAR-g mutant mouse pups had similar phenotype compared with wild-type pups.......................................35
PpargP465L/+ mouse pups showed similar degree of grey matter injury after hypoxic ischemia compared with wild-type pups.................................................36
PpargP465L/+ pups had aggravated white matter injury after hypoxic ischemia..........................................36
PpargP465L/+ pups had more activated microglia/macrophages after hypoxic ischemia....................................37
PpargP465L/+ pups had increased TNF-a �nexpression after hypoxic ischemia..........................................37
Enhanced blood-brain barrier damage after hypoxic ischemia in PpargP465L/+ pups......................................38
Increased cell apoptosis after hypoxic ischemia in PpargP465L/+ pups.........................................38
DISCUSSION................................................39
REFERENCES................................................44
APPENDIX..................................................52
BIOGRAPHY NOTE............................................80
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