近年來有許多證據表明，神經發炎反應與神經退化性疾病，如：阿茲海默症(Alzheimer′s disease, AD)和帕金森氏症(Parkinson′s disease, PD)的發病機制密切相關。中樞神經系統(CNS)中微膠細胞(microglia)的活化被認為是神經發炎的指標。活化的微膠細胞所釋放的促發炎細胞因子，會引起神經發炎和神經細胞死亡。因此，抑制微膠細胞活化被認為是神經保護作用的重要指標。Fenofibrate是fibrate類藥物的一種，可單獨或與statins一起用於治療高膽固醇(hypercholesterolemia)和三酸甘油酯(hypertriglyceridemia)，具有抗癌和抗發炎的作用。然而人們對中樞神經系統中有益的抗炎作用機制知之甚少。在這項研究中，我們證實Fenofibrate會抑制一氧化氮(Nitric oxide, NO)的釋放和inducible nitric oxide synthase i(NOS)和cyclooxygenase (COX)-2，以及微膠質細胞其他的促發炎細胞因子的表現；另外，Fenofibrate的治療還誘導微膠質細胞中的抗發炎因子表現。我們實驗室之前的研究發現，Sonic hedgehog (SHH)和erythropoietin (EPO)可誘導微膠質細胞中Brain-derived neurotrophic factor (BDNF)的抗發炎作用；此外，經由naringenin所誘導的Suppressor of cytokine signaling (SOCS)表現會減少促發炎細胞因子的表現；並且，誘導Heme oxygenase (HO)-1表現可產生神經保護作用，且與抵抗微膠細胞的發炎反應有很大的關係。SHH和Sirtuin (SIRT) 1的表現和Fenofibrate的抗發炎作用受到signal transducer and activator of transcription (STAT) 3和focal adhesion kinase (FAK)的調節。除此之外，Fenofibrate對於zymosan和LPS誘導的微膠質細胞活化引起的神經毒殺具有保護作用。我們的研究表明，Fenofibrate抑制iNOS和COX-2表現是通過STAT3和FAK訊號通路去誘導 SHH和SIRT1活化。因此，參與抗神經發炎反應和神經保護作用的Fenofibrate可能是具有治療發炎相關疾病的?力藥物。
Accumulating evidence suggests that neuroinflammation is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer′s disease and Parkinson′s disease. Microglia activation in the control nervous system (CNS) is considered to be the hallmark of neuroinflammation. Activated microglia release pro-inflammatory mediators which cause neuroinflammation and progressive neurodegeneration. Therefore, inhibited microglial activation is considered as an important novel strategy for the developing of neuroprotection. Fenofibrate, a drug of the fibrate class and used alone or along with statins in the treatment of hypercholesterolemia and hypertriglyceridemia, has been reported to exert anticancer and anti-inflammatory properties. However, the mechanism of its beneficial anti-inflammatory effects in the central nervous system (CNS) is poorly understood. In this study, we demonstrated that fenofibrate inhibited the release of nitric oxide (NO), the expression of inducible nitric oxide synthase i(NOS) and cyclooxygenase (COX)-2 as well as proinflammatory cytokines in microglial cells. And then, treatment of fenofibrate also induced anti-inflammatory cytokine expression in microglia. Our previous studies show that Sonic hedgehog (SHH) and erythropoietin (EPO) are involved in anti-neuroinflammatory effects of Brain-derived neurotrophic factor (BDNF) in microglia. We also demonstrated that Suppressor of cytokine signaling (SOCS) plays a key role in naringenin-mediated downregulation of pro-inflammatory cytokines in microglia. Furthermore, our previous finding also showed that induction of Heme oxygenase (HO)-1 regulates neuroinflammatory homeostasis. Here, we found that treatment of fenofibrate induced SHH and Sirtuin (SIRT) 1 expression in microglia. Moreover, the enhancement of SHH and SIRT1 were regulated by Signal transducer and activator of transcription (STAT) 3 and focal adhesion kinase (FAK). Besides, fenofibrate exerted anti-neuroinflammation caused by zymosan and LPS stimulation in microglia. Our findings suggest that fenofibrate-inhibited microglial-associated neuroinflammation are mediated by SHH and SIRT1 activation through STAT3 and FAK signaling pathway. Our results also indicated that fenofibrate regulates in microglial cells and fenofibrate might be a potential agent for treatment of inflammation-associated disorders.
