Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway
Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway
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DOI：
10.1007/s11302-015-9475-2
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发表时间：
2015-12-01
影响因子：
3.5
通讯作者：
Quincozes-Santos, Andre
中科院分区：
文献类型：
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作者：
Bellaver, Bruna;Souza, Debora Guerini;Quincozes-Santos, Andre
鸟苷是一种以鸟嘌呤为基础的嘌呤类物质，是星形胶质细胞释放的一种细胞外信号分子，已在多种体内和体外损伤模型中被证明促进中枢神经系统的防御。本课题组最近证实鸟苷通过将血红素加氧酶-1(HO-1)信号通路与对叠氮诱导的氧化应激的保护联系起来，在C6星形胶质细胞系中显示出神经胶质细胞的保护作用。星形胶质细胞过度激活会引发脑部炎症，这种情况与许多神经疾病的发展密切相关。这些细胞感知和放大来自小胶质细胞的炎症信号，和/或启动与转录因子密切相关的炎症介质的释放，如受HO-1调控的核因子kappaB(NF Kappa B)。星形胶质细胞也表达Toll样受体(Toll-like Receptor，TLRs)；TLRs特异性识别脂多糖(LPS)，它已被广泛用于实验研究炎症反应。本研究旨在了解鸟苷对脂多糖诱导的原代培养的海马星形胶质细胞的炎症和氧化损伤的保护作用机制。脂多糖处理星形胶质细胞可导致致炎细胞因子水平升高、核因子-kappaB活化、线粒体功能障碍、氧/氮水平升高和抗氧化防御水平下降。鸟苷可以通过激活HO-1通路保护海马星形胶质细胞免受内毒素诱导的细胞毒性，从而阻止这些效应的发生。此外，鸟苷的抗炎作用不依赖于腺苷能系统。这些结果突出了鸟苷对神经炎性相关疾病的潜在作用。
Guanosine, a guanine-based purine, is an extracellular signaling molecule that is released from astrocytes and has been shown to promote central nervous system defenses in several in vivo and in vitro injury models. Our group recently demonstrated that guanosine exhibits glioprotective effects in the C6 astroglial cell line by associating the heme oxygenase-1 (HO-1) signaling pathway with protection against azide-induced oxidative stress. Astrocyte overactivation contributes to the triggering of brain inflammation, a condition that is closely related to the development of many neurological disorders. These cells sense and amplify inflammatory signals from microglia and/or initiate the release of inflammatory mediators that are strictly related to transcriptional factors, such as nuclear factor kappa B (NF kappa B), that are modulated by HO-1. Astrocytes also express toll-like receptors (TLRs); TLRs specifically recognize lipopolysaccharide (LPS), which has been widely used to experimentally study inflammatory response. This study was designed to understand the glioprotective mechanism of guanosine against the inflammatory and oxidative damage induced by LPS exposure in primary cultures of hippocampal astrocytes. Treatment of astrocytes with LPS resulted in deleterious effects, including the augmentation of pro-inflammatory cytokine levels, NF kappa B activation, mitochondrial dysfunction, increased levels of oxygen/nitrogen species, and decreased levels of antioxidative defenses. Guanosine was able to prevent these effects, protecting the hippocampal astrocytes against LPS-induced cytotoxicity through activation of the HO-1 pathway. Additionally, the anti-inflammatory effects of guanosine were independent of the adenosinergic system. These results highlight the potential role of guanosine against neuroinflammatory-related diseases.