Abstract
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.
Highlights
Diabetes mellitus is a serious metabolic disorder characterized by elevated blood glucose levels due to improper insulin function (Ramos-Rodriguez et al, 2014)
Administration of 10 mg/kg gliquidone significantly reduced the LPS-induced increases in Iba-1 intensity, Iba-1-positive cells, and Iba-1-labeled area only in the hippocampal CA3 region (Figures 1C–E). These results indicated that a gliquidone dose of 20 mg/kg more effectively downregulates LPS-mediated microgliosis and changes in microglial kinetics and morphology in the wildtype mouse brain
Since gliquidone downregulated LPS-evoked proinflammatory cytokine levels and nuclear STAT3 and NF-κB phosphorylation in primary astrocytes, we further examined the effects of gliquidone on LPS-induced astrocytic NLRP3 inflammasome activation
Summary
Diabetes mellitus is a serious metabolic disorder characterized by elevated blood glucose levels (hyperglycemia) due to improper insulin function (Ramos-Rodriguez et al, 2014). Type 2 diabetes and insulin resistance can lead to peripheral meta-inflammation and an overproduction of proinflammatory cytokines (Ferreira et al, 2014). Clusters of proteins that are differentially regulated in type 2 diabetes have been linked to neuroinflammation and related neurodegenerative diseases, including Alzheimer’s disease (AD) (Mittal et al, 2016). Clinical studies have shown that some classes of diabetes medications can rescue both glycemic control and inflammation-linked deficits, providing benefits for cognitive function and reducing dementia risk (Chatterjee and Mudher, 2018; Weinstein et al, 2019; Akimoto et al, 2020). The molecular mechanisms by which diabetes medications affect neuroinflammatory responses have not been fully elucidated
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