Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Neurotox Res. 2020 Jan;37(1):111-125. doi: 10.1007/s12640-019-00102-1. Epub 2019 Sep 4.
Neuroinflammation is a major factor in the pathogenesis of various neurodegenerative diseases. Microglia are resident macrophages that act as key mediators of inflammation in the brain. In response to inflammatory stimuli including lipopolysaccharide (LPS), microglial activation occurs immediately. Overproduction of inflammatory mediators released by activated microglia contributes to neuron damage in neurodegenerative disease. Therefore, identification of a compound that has anti-inflammatory activities and inhibits microglial activation may be an alternative therapeutic approach for the treatment of neurodegenerative diseases. Cyanidin-3-O-glucoside (C3G), a type of anthocyanin, possesses powerful anti-inflammatory activities. In this study, the anti-inflammatory effects of C3G were investigated in LPS-stimulated BV2 microglia. The results indicate that pretreatment with C3G significantly suppresses microglial activation and the production of neurotoxic mediators including nitric oxide (NO), prostaglandin E2 (PGE), and pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6) in LPS-activated BV2 cells. Moreover, C3G downregulates the gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines via the suppression of NF-κB and p38 MAPK signaling pathways. Furthermore, a co-culture system to determine the indirect neuroprotective effects of C3G was used. Results demonstrated that conditioned medium (CM) from LPS-stimulated BV2 cells can promote the apoptosis of differentiated pheochromocytoma (PC12) cells through the activation of caspase-3, while C3G pretreatment in BV2 microglia can protect differentiated PC12 cells from microglial activation-induced apoptosis. Therefore, C3G may be a potential therapeutic agent for the treatment and prevention of neurodegenerative diseases associated with microglial activation.
神经炎症是多种神经退行性疾病发病机制中的一个主要因素。小胶质细胞是驻留巨噬细胞，是大脑炎症的关键介质。在受到包括脂多糖（LPS）在内的炎症刺激后，小胶质细胞会立即被激活。激活的小胶质细胞释放的炎症介质过度产生，导致神经退行性疾病中的神经元损伤。因此，鉴定具有抗炎活性并抑制小胶质细胞激活的化合物可能是治疗神经退行性疾病的一种替代治疗方法。矢车菊素-3-O-葡萄糖苷（C3G）是一种花色苷，具有强大的抗炎活性。在这项研究中，研究了 C3G 在 LPS 刺激的 BV2 小胶质细胞中的抗炎作用。结果表明，C3G 预处理可显著抑制 LPS 激活的 BV2 细胞中小胶质细胞的激活和神经毒性介质（包括一氧化氮（NO）、前列腺素 E2（PGE2）和促炎细胞因子如白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6））的产生。此外，C3G 通过抑制 NF-κB 和 p38 MAPK 信号通路下调诱导型一氧化氮合酶（iNOS）、环加氧酶-2（COX-2）和促炎细胞因子的基因表达。此外，还使用共培养系统来确定 C3G 的间接神经保护作用。结果表明，LPS 刺激的 BV2 细胞的条件培养基（CM）可通过激活 caspase-3 促进分化的嗜铬细胞瘤（PC12）细胞的凋亡，而 C3G 在 BV2 小胶质细胞中的预处理可保护分化的 PC12 细胞免受小胶质细胞激活诱导的凋亡。因此，C3G 可能是一种有潜力的治疗剂，可用于治疗和预防与小胶质细胞激活相关的神经退行性疾病。
