Cargando…

The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome

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 o...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Jieun, Park, Jin-Hee, Shah, Keshvi, Mitchell, Scott John, Cho, Kwangwook, Hoe, Hyang-Sook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587901/
https://www.ncbi.nlm.nih.gov/pubmed/34776934
http://dx.doi.org/10.3389/fnagi.2021.754123
_version_ 1784598290420989952
author Kim, Jieun
Park, Jin-Hee
Shah, Keshvi
Mitchell, Scott John
Cho, Kwangwook
Hoe, Hyang-Sook
author_facet Kim, Jieun
Park, Jin-Hee
Shah, Keshvi
Mitchell, Scott John
Cho, Kwangwook
Hoe, Hyang-Sook
author_sort Kim, Jieun
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8587901
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-85879012021-11-13 The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome Kim, Jieun Park, Jin-Hee Shah, Keshvi Mitchell, Scott John Cho, Kwangwook Hoe, Hyang-Sook Front Aging Neurosci Aging Neuroscience 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. Frontiers Media S.A. 2021-10-29 /pmc/articles/PMC8587901/ /pubmed/34776934 http://dx.doi.org/10.3389/fnagi.2021.754123 Text en Copyright © 2021 Kim, Park, Shah, Mitchell, Cho and Hoe. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging Neuroscience
Kim, Jieun
Park, Jin-Hee
Shah, Keshvi
Mitchell, Scott John
Cho, Kwangwook
Hoe, Hyang-Sook
The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome
title The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome
title_full The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome
title_fullStr The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome
title_full_unstemmed The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome
title_short The Anti-diabetic Drug Gliquidone Modulates Lipopolysaccharide-Mediated Microglial Neuroinflammatory Responses by Inhibiting the NLRP3 Inflammasome
title_sort anti-diabetic drug gliquidone modulates lipopolysaccharide-mediated microglial neuroinflammatory responses by inhibiting the nlrp3 inflammasome
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8587901/
https://www.ncbi.nlm.nih.gov/pubmed/34776934
http://dx.doi.org/10.3389/fnagi.2021.754123
work_keys_str_mv AT kimjieun theantidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT parkjinhee theantidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT shahkeshvi theantidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT mitchellscottjohn theantidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT chokwangwook theantidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT hoehyangsook theantidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT kimjieun antidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT parkjinhee antidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT shahkeshvi antidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT mitchellscottjohn antidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT chokwangwook antidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome
AT hoehyangsook antidiabeticdruggliquidonemodulateslipopolysaccharidemediatedmicroglialneuroinflammatoryresponsesbyinhibitingthenlrp3inflammasome