Kim Jieun, Park Jin-Hee, Shah Keshvi, Mitchell Scott John, Cho Kwangwook, Hoe Hyang-Sook
Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, South Korea.
UK-Dementia Research Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Front Aging Neurosci. 2021 Oct 29;13:754123. doi: 10.3389/fnagi.2021.754123. eCollection 2021.
The sulfonylurea drug gliquidone is FDA approved for the treatment of type 2 diabetes. Binding of gliquidone to ATP-sensitive potassium channels (SUR1, Kir6 subunit) in pancreatic β-cells increases insulin release to regulate blood glucose levels. Diabetes has been associated with increased levels of neuroinflammation, and therefore the potential effects of gliquidone on micro- and astroglial neuroinflammatory responses in the brain are of interest. Here, we found that gliquidone suppressed LPS-mediated microgliosis, microglial hypertrophy, and proinflammatory cytokine COX-2 and IL-6 levels in wild-type mice, with smaller effects on astrogliosis. Importantly, gliquidone downregulated the LPS-induced microglial NLRP3 inflammasome and peripheral inflammation in wild-type mice. An investigation of the molecular mechanism of the effects of gliquidone on LPS-stimulated proinflammatory responses showed that in BV2 microglial cells, gliquidone significantly decreased LPS-induced proinflammatory cytokine levels and inhibited ERK/STAT3/NF-κB phosphorylation by altering NLRP3 inflammasome activation. In primary astrocytes, gliquidone selectively affected LPS-mediated proinflammatory cytokine expression and decreased STAT3/NF-κB signaling in an NLRP3-independent manner. These results indicate that gliquidone differentially modulates LPS-induced microglial and astroglial neuroinflammation in BV2 microglial cells, primary astrocytes, and a model of neuroinflammatory disease.
磺脲类药物格列喹酮已获美国食品药品监督管理局（FDA）批准用于治疗2型糖尿病。格列喹酮与胰腺β细胞中的ATP敏感性钾通道（SUR1、Kir6亚基）结合，可增加胰岛素释放，从而调节血糖水平。糖尿病与神经炎症水平升高有关，因此格列喹酮对大脑中微胶质细胞和星形胶质细胞神经炎症反应的潜在影响备受关注。在此，我们发现格列喹酮可抑制野生型小鼠中脂多糖（LPS）介导的小胶质细胞增生、小胶质细胞肥大以及促炎细胞因子COX-2和白细胞介素-6（IL-6）的水平，对星形胶质细胞增生的影响较小。重要的是，格列喹酮可下调野生型小鼠中LPS诱导的小胶质细胞NLRP3炎性小体和外周炎症。对格列喹酮影响LPS刺激的促炎反应的分子机制进行研究表明，在BV2小胶质细胞中，格列喹酮可显著降低LPS诱导的促炎细胞因子水平，并通过改变NLRP3炎性小体的激活来抑制细胞外信号调节激酶（ERK）/信号转导和转录激活因子3（STAT3）/核因子κB（NF-κB）的磷酸化。在原代星形胶质细胞中，格列喹酮以不依赖NLRP3的方式选择性地影响LPS介导的促炎细胞因子表达，并降低STAT3/NF-κB信号传导。这些结果表明，格列喹酮可在BV2小胶质细胞、原代星形胶质细胞以及神经炎症疾病模型中差异性地调节LPS诱导的小胶质细胞和星形胶质细胞神经炎症。
