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Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β

Title
Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/β
Author(s)
Park, Jin-HeeHwang, Jeong-WooLee, Hyun-juJang, Geum MiJeong, Yoo JooCho, JoonhoSeo, JinsooHoe, Hyang-Sook
Issued Date
2023-06
Citation
Frontiers in Immunology, v.14
Type
Article
Author Keywords
lomerizineneuroinflammationtauopathyAlzheimer’s diseaseDYRK1ANLRP3
Keywords
ACTIVATIONMICROGLIAPHOSPHORYLATIONCYTOKINESPATHOLOGYDISEASE
ISSN
1664-3224
Abstract
Introduction: Lomerizine is a calcium channel blocker that crosses the blood–brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet.
Methods: To assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer’s disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice.
Results: In BV2 microglial cells, lomerizine pretreatment significantly reduced LPS-evoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/β and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice.
Discussion: These data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases.
URI
http://hdl.handle.net/20.500.11750/46138
DOI
10.3389/fimmu.2023.1150940
Publisher
Frontiers Media S.A.
Related Researcher
  • 서진수 Seo, Jinsoo 뇌과학과
  • Research Interests iPSC; Alzheimer's disease; Neurodegeneration; Synapse; Neuroscience
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Appears in Collections:
Department of Brain Sciences Laboratory of Aging Brain 1. Journal Articles

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