PGE2與15d-PGJ2為前列腺素 (Prostaglandins, PGs) 的家族之一。 PGE2研究證實具促進發炎反應（inflammation）、促使細胞素 (cytokines) 分泌、加強血管收縮；在腦部缺血模式(cerebral ischemia model) 及lipopolysaccharide (LPS) 傷害神經細胞，PGE2具有保護神經細胞 （neuroprotection）的功能。15d-PGJ2可活化下游PPAR-g (Peroxisome proliferators-activated receptor-g) 訊息傳遞路徑以清除胞內氧化分子（reactive oxygen species, ROS）。海人草酸（Kainate, KA）對腦部組織產生發炎反應，並出現退化的神經細胞及引起癲癇 (epilepsy)。為探討PGs在KA造成的neurotoxicity下是否具有neuroprotection的效用，本實驗將KA與PGE2或15d-PGJ2同時微注射（microinjection）入老鼠海馬迴 (hippocampus) CA3 region，再以 Cresyl violet、Fluoro-Jade B 及免疫螢光雙重染色偵測退化的神經細胞數目、IL-1b 表現，及微膠細胞 (microglia)數目變化，並以western blot 分析COX-2、HO-1蛋白質表現。Fluoro-Jade B染色結果，KA單獨處理的海馬迴組織出現退化性神經細胞；而由 Cresyl violet 染色結果發現PGE2比15d-PGJ2具有提高神經細胞數目的功能。KA單獨處理誘導海馬迴CA3 region 大量表現 IL-1b 的細胞，同時處理PGE2並不會改變表現 IL-1b 的細胞數目。免疫螢光雙重染色證實表現IL-1b 的細胞是星狀細胞 (astrocytes)，並非microglia。PGE2 / KA處理的海馬迴組織，其microglia數目低於KA單獨處理。KA單獨處理增加COX-2；但PGE2 / KA處理則會降低COX-2的表現，且增加HO-1的生成量。總結在KA誘導的neurotoxicity，PGE2 可減少microglia數目及inflammatory protein-COX-2生成，而增加抗氧化蛋白HO-1的生成量，故推測PGE2比15d-PGJ2更具neuroprotection的效果。

Prostaglandin E2 (PGE2), a product of arachidonic acid cyclooxygenase (COX) metabolism, has been known as an important inflammatory mediator. By contrast, 15d-PGJ2, a non-enzymatic metabolites of prostaglandin D2 (PGD2) and a specific PPAR-g agonist, is known to repress several inflammatory responses. Both PGD2 and PGE2 are abundant PGs in the brain. Despite the classic role of PGE2 as a proinflammatory molecule, much in vivo and in vitro evidence have demonstrated that exogenous PGE2 may protect glutamate toxicity in neurons. The present work examines whether exogenous PGE2 or 15d-PGJ2 is able to protect kainate-induced cell damage in the rat hippocampus. Infusion of kainate to rat hippocampal CA3 significantly induced neuronal damage as evidenced by (1) presence of Fluoro-Jade B positive cells (2) increment of IL-1b positive cells and COX-2 expression (3) increment of activated microglia (ED1 positive) number (4) reduction of neuronal number. Co-infusion of PGE2 with kainate (0.2mg / ml / CA3 region) to hippocampal CA3 alleviates kainate-induced neuronal loss and microglial activation. Furthermore, kainate-induced COX-2 expression was reduced by PGE2, while heme oxygenase-1 (antioxidative stress protein) expression was increased by PGE2. By contrast, co-infusion of 15d-PGJ2 with kainate did not have protective effect on kainate-induced toxicity. Taken together, PGE2, but not 15d-PGJ2, effectively protect hippocampal CA3 cells from kainate-induced damage.

目次
中文摘要……………………………………………………….. I
英文摘要……………………………………………………….. III
目次…………………………………………………………….. IV
圖目錄………………………………………………………….. VII
表目錄………………………………………………………….. IX
壹、前言……………………………………………………… 1
一、海馬結構……………………………………………. 1
二、海人草酸……………………………………………. 4
三、癲癇…………………………………………………. 5
四、海人草酸接受器……………………………………. 7
五、KA對中樞神經系統所造成的影響……………….. 9
六、發炎反應……………………………………………. 10
七、神經膠細胞及其在發炎反應上的功能……………. 11
八、前列腺素……………………………………………. 12
九、環氧化脢……………………………………………. 14
十、前列腺素E2…………………………………………. 15
十一、15d-PGJ2與其功能……………………………….. 16
貳、研究目的………………………………………………… 19
參、實驗流程………………………………………………… 21
肆、實驗材料與方法………………………………………… 22
一、實驗動物……………………………………………. 22
二、海馬迴組織微注射手術之動物分組………………. 22
三、立體定位手術方法…………………………………. 22
四、癲癇行為測量………………………………………. 26
五、海馬迴組織擷取……………………………………. 27
六、灌流與固定…………………………………………. 28
七、包埋與切片…………………………………………. 28
八、Cresyl violet stain (Nissl stain)….……….. 29
九、Fluoro-Jade B stain……………………………... 29
十、免疫組織化學染色…………………………………. 30
十一、免疫螢光雙重染色……………………………….. 31
十二、染色細胞量化分析……………………………….. 33
十三、西方點墨法……………………………………….. 33
十四、統計分析………………………………………….. 37
伍、實驗結果………………………………………………… 38
一、不同的 KA 濃度與老鼠海馬迴 CA3 受損程度的關係
………………………………………………………. 38
二、KA 誘導海馬迴神經細胞進行neurodegeneraiton
………………………………………………………. 38
三、KA產生的neurodegeneration是否發生於神經細胞上
………………………………………………………. 39
四、KA與兩種不同PGs微注射於老鼠海馬迴中造成神經細胞存活狀態……………………………………………. 39
五、KA與PGE2對於CA3 region所造成之inflammation情形
………………………………………………………. 41
六、KA與PGE2對於CA3 region所誘導之microglia情形
………………………………………………………. 42
七、KA與PGE2在不同蛋白質表現上所造成的差異… 43
陸、討論……………………………………………………… 44
柒、結論……………………………………………………… 51
捌、參考文獻………………………………………………… 53
玖、實驗結果圖表…………………………………………… 69

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