探討Caffeic acid phenethyl ester及Dynasore抑制微膠細胞活化之機轉及其於活體保護腦部發炎作用的效果

Investigation of the inhibitory mechanisms of Caffeic acid phenethyl ester and Dynasore on microglial activation and their protective effects on neuroinflammation in vivo

陳冠蓉(Kuan-Jung Chen)

指導教授 ： 蕭哲志

臺北醫學大學/醫學院/醫學科學研究所/碩士(2010年)

https://doi.org/10.6831/TMU.2010.00139

摘要

在神經發炎性疾病或是神經退化性疾病中，神經膠細胞的活化及其引起的發炎反應扮演了疾病發展中重要的角色。活化的神經膠細胞所分泌的各種前發炎細胞激素及神經致毒媒介會導致神經細胞的死亡，藉由抑制神經膠細胞的過度活化可達到減緩神經性疾病的發展。
本篇研究顯示，在LPS刺激微膠細胞實驗中，CAPE與Dynasore可以抑制iNOS的蛋白表現，也可抑制IκBα的分解而進一步抑制NF-κB的次單位p65進入細胞核內作用。另外，CAPE亦能抑制MAPK訊息傳遞路徑之ERK的磷酸化，而Dynasore則可抑制MAPK訊息傳遞路徑之p38、ERK及JNK的磷酸化。
活體實驗中，CAPE能抑制LPS引起腦部發炎所誘導的COX-2及MMP-9活性，以及腦內出血後所誘導的iNOS、COX-2及MMP-9活性；CAPE亦對腦部發炎引起的血腦屏障通透度增加及腦內出血後的腦水腫有改善作用。Dynasore雖只對腦內出血後的MMP-9活性有抑制作用，但卻也能改善腦部發炎引起的血腦屏障通透度增加及腦內出血後的腦水腫。
上述結果顯示出在中樞神經系統中，CAPE及Dynasore或許可調控微膠細胞的活化，減少其在受刺激後所產生的iNOS，因而可降低發炎反應；此外，亦能改善腦部發炎及腦內出血後的病理現象。

關鍵字

微膠細胞 ； 腦部發炎

並列摘要

Glial activation plays an important role in the pathogenesis of neuroinflammatory and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may contribute to neuronal cell death. Inhibition of glial activation may alleviate neurodegeneration under these conditions.
In LPS-induced microglial activation, it was shown that CAPE and Dynasore both attenuated the expression of iNOS protein. Moreover, CAPE and Dynasore inhibited IκBα degradation, and then could affect the nuclear translocation of the p65 subunit of NF-κB. Additionally, the phosphorylation of ERK in mitogen-activated protein kinase was inhibited by CAPE. Dynasore inhibited the activation of all mitogen-activated protein kinase subfamily such as p38, ERK, and JNK.
In vivo experiments suggested that CAPE inhibited the expression of COX-2 protein and enzymatic activity of MMP-9 in LPS-mediated neuroinflammation. On the other hand, this compound could inhibit the expression of iNOS and COX-2 protein and activity of MMP-9 in collagenae-induced intracerebral hemorrhage. In addition, CAPE exerted beneficial effects on increased BBB permeability caused by LPS- induced neuroinflammation and on brain edema after intracerebral hemorrhage. Moreover, Dynasore could inhibit the increase of MMP-9 activiy after intracerebral hemorrhage, and it excerted the same beneficial effects on increased BBB permeability and brain edema.
In summary, these results imply that CAPE and Dynasore may attenuate the activation of microglia and then inhibit the expression of inflammatory mediators, and alleviate the inflammatory reaction in the central nervous system. Moreover, both bioactive compounds exert the beneficial effects on pathogenesis occurred after neuroinflammation and intracerebral hemorrhage.

並列關鍵字

Caffeic acid phenethyl ester ； Dynasore ； neuroinflammation

參考文獻

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