| 摘要: | 大腦中的慢性發炎在神經退化性疾病如阿茲海默症(AD)、帕金森氏症(PD)等疾病中扮演著重要的角色，而神經小膠質細胞(microglia)是中樞神經系統中主要的免疫巨噬細胞(macrophage)，當中樞神經系統受到外在損傷可能發生神經退化性疾病，小膠質細胞就很容易被活化，產生大量的前發炎因子(pro-inflammatory mediators)，如一氧化氮(NO)、腫瘤壞死因子-a(TNF-a)及介白質素-1b(IL-1b)等等；若一直持續活化是會對中樞神經系統造成傷害，不斷擴大發炎反應，影響神經再生。
近年來，運用在各種癌症上的標靶藥物越來越多，除了一般常見的蛋白質分子標靶藥物外，更有文獻發現稀有貴重金屬銥（Iridium, Ir）可以抑制癌症，能做為未來治療癌症的潛在藥物。Ir化合物屬於platinum系列的衍生物，因為它不具細胞毒性的抗癌效果所以成為Pt化合物的潛在替代品。本實驗室與印度大學合作，Marappan Velusamy教授合成了一系列的Ir化合物，經由初步篩選後選擇了Ir-3、Ir-6、Ir-11三種藥物來做抗發炎活性之比較。2015年有文獻指出Ir化合物具有潛在的抗菌及抗癌作用，Jingwen Zhang等人於2017年發表論文指出Ir藥物在macrophage的抗發炎表現，而本實驗室於2018年發現Ir-3、Ir-6、Ir-11具有抗血小板凝集之效果，然而過去曾未有研究將此藥物作用在microglia，相關抗腦神經發炎之功能並未清楚，因此在本篇研究中我們利用小鼠的microglia細胞株，經由脂多醣體(lipopolysaccharide，LPS)刺激使細胞活化產生發炎反應，以探討比較三種Ir的衍生化合物Ir-3、Ir-6、Ir-11的化學結構活性關係，而實驗發現Ir-6藥物在10uM可有效降低LPS在microglia中所引發的發炎反應，包含iNOS、TNF-a、IL-1b等細胞因子，因此Ir化合物在microglia之抗發炎效果可能成為未來腦神經治療潛在的抗發炎藥物。
Chronic inflammation in the brain plays a critical role in major neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Microglia, the resident macrophages and intrinsic components of the central nervous system (CNS), appear to be the main effectors in this pathological process. Iridium (Ir) compounds are potential alternatives to platinum compounds, since they exert promising anticancer effects without cellular toxicity. Recent studies found that Ir compounds show potent antiplatelet properties. However, its functions on microglia and the related neuroinflammation remain unknown. In this dissertation, the comparative anti-neuroinflammatory effect of three newly synthesized iridium (Ir) compounds, Ir (Cp*) 1-(2-pyridyl)-3-(3-methoxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-3), [Ir(Cp*)1-(2-pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-6) and [Ir(Cp*)1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-11) was investigated against lipopolysaccharide (LPS)-induced BV2 microglial cells. The morphology of control BV2 microglia showed small soma with distal arborization, characteristic of “ramified” microglia. LPS-treated BV2 microglia had fewer branches that were shorter and or appeared to be resorbed into the cell body. The mRNA expression of inflammatory effector enzymes cyclooxygenase (COX-2) and induced nitric oxide synthase (iNOS), pro-inflammatory cytokine of tumor necrosis factor-α (TNF-α), interleukin (IL)-1α, IL-1β, and IL-6 were significantly elevated in LPS-stimulated BV2 cells. Moreover, the anti-inflammatory cytokines of Arg-1 and IL-10 were markedly decreased BV2 cells stimulated by LPS. Western blot analysis shows that among the tested three Ir- compounds, only Ir-6 attenuated the expression of iNOS and IL-1β. These results suggest that Ir-6 could be used as a novel anti-inflammatory and microglia-modulating drug for neurodegenerative diseases. |
