探討N-hydroxycinnamoylphenalkylamides衍生物抑制小膠質細胞活化之機轉及其於活體抗腦部發炎的效果

Investigation of the inhibitory mechanisms of N-hydroxycinnamoylphenalkylamides analogue on microglia activation and its anti-neuroinflammatory effects in vivo

林凡立(Fan-Li Lin)

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(2009年)

https://doi.org/10.6831/TMU.2009.00114

摘要

在各種腦神經疾病，例如中風後腦損傷或多發性硬化症、阿茲海默症、帕金森氏症、人類免疫缺乏病毒相關失憶症等神經退化性疾病中，神經膠細胞的活化及發炎反應扮演了疾病發展重要的角色。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以達到減緩神經退化性疾病的發展。本篇研究顯示，在脂多醣體刺激小膠質細胞實驗中，EK8 (20μM)可以抑制一氧化氮合成酶(iNOS)的蛋白表現，也可抑制IκB的分解而進一步抑制NF-κB的次單位p65進入細胞核內作用；另外尚能抑制mitogen-activated protein kinase訊息傳遞路徑之JNK及p38的磷酸化。離體實驗中，EK8明顯抑制腦脂質過氧化反應並具清除自由基之效能。另外EK8能減少腦部注射lipopolysaccharide (LPS)所誘發之星狀膠細胞(astrocyte)過度增生及硝基酪氨酸(nitrotyrosine)的生成。
因此，由上述這些結論指出在中樞神經系統中，EK8藉由調控神經膠細胞活性以及抗氧化能力，提供了神經細胞抗發炎及神經保護之特性。

關鍵字

小膠質細胞 ； 星狀膠細胞 ； 一氧化氮合成酶腦發炎 ； 顱內出血 ； 脂多醣體 ； 膠原蛋白分解酶基質金屬蛋白分解酶自由基

並列摘要

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as post-stroke brain injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and HIV dementia. 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.
The results showed that EK8 (20μM) attenuated the expression of inducible nitric oxide synthase in the lipopolysaccharide-stimulated microglia cells. Moreover, EK8 inhibited IκB degradation, nuclear translocation of the p65 subunit of NF-κB, and phosphorylation of JNK and p38 in mitogen-activated protein kinase (MAPK) signaling. Ex vivo experiment suggested that EK8 inhibited lipid peroxidation and scavenged the free radicals significantly. In addition, EK8 decreased astrocyte hypertrophy and nitrotyrosine formation in LPS-injected brain.
Therefore, these results imply that EK8 have anti-inflammatory and neuroprotective effects in the central nervous system by modulating glial activation and anti-oxidation activity.

並列關鍵字

microglia ； astrocyte ； iNOS ； brain inflammation ； intracerebral hemorrhage ； lipopolysaccharide ； collagenase ； matrix metalloproteinase ； free radicals

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