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

Front Immunol. 2023 Jun 26:14:1150940. doi: 10.3389/fimmu.2023.1150940. eCollection 2023.

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.

Keywords: Alzheimer’s disease; DYRK1A; NLRP3; lomerizine; neuroinflammation; tauopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / drug therapy
  • Animals
  • Cytokines
  • Dyrk Kinases
  • Glycogen Synthase Kinase 3*
  • Inflammation / drug therapy
  • Lipopolysaccharides
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein*
  • Neuroinflammatory Diseases
  • tau Proteins

Substances

  • Cytokines
  • Lipopolysaccharides
  • lomerizine
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Glycogen Synthase Kinase 3
  • tau Proteins

Grants and funding

This work was supported by the KBRI basic research program through KBRI funded by the Ministry of Science, ICT & Future Planning (grant numbers 23-BR-02-03, 23-BR-03-05, 23-BR-05-02, and 23-BR-03-01, H-SH) and the DGIST R&D program of the Ministry of Science and ICT (22-CoE-BT-01, JS).