Lomerizine inhibits LPS-mediated neuroinflammation and tau hyperphosphorylation by modulating NLRP3, DYRK1A, and GSK3α/βopen access
- Authors
- Park, Jin-Hee; Hwang, Jeong-Woo; Lee, Hyun-ju; Jang, Geum Mi; Jeong, Yoo Joo; Cho, Joonho; Seo, Jinsoo; Hoe, Hyang-Sook
- Issue Date
- Jun-2023
- Publisher
- Frontiers Media S.A.
- Keywords
- lomerizine; neuroinflammation; tauopathy; Alzheimer' s disease; DYRK1A; NLRP3
- Citation
- Frontiers in Immunology, v.14
- Journal Title
- Frontiers in Immunology
- Volume
- 14
- URI
- http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/119
- DOI
- 10.3389/fimmu.2023.1150940
- ISSN
- 1664-3224
- Abstract
- IntroductionLomerizine 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. MethodsTo 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. ResultsIn 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 GSK3 & alpha;/& beta; and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice. DiscussionThese data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases.
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