Structurally Distinct Nurr1 Ligands Exhibit Different Pharmacological Characteristics in Regulating Inflammatory Responses of Microglial BV-2 Cells

Biol Pharm Bull. 2024;47(11):1937-1945. doi: 10.1248/bpb.b24-00644.

Abstract

Nurr1 (NR4A2) is a member of nuclear receptor superfamily that regulates gene transcription in midbrain dopaminergic neurons and also inhibits nuclear factor-κB-mediated inflammatory responses in brain microglial cells. To date, various compounds have been reported to stimulate transcriptional activity of Nurr1 on neuronal genes, but their anti-inflammatory actions are poorly characterized. The present study examined the effects of three kinds of Nurr1 ligands, amodiaquine, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)-methane (C-DIM12) and 5-chloronaphthalen-1-amine (5-CNA), on inflammatory responses of microglial BV-2 cells. Lipopolysaccharide (LPS)-induced upregulation of interleukin-1β mRNA and tumor necrosis factor α mRNA was inhibited by all three compounds, whereas upregulation of interleukin-6 mRNA and inducible nitric oxide synthase (iNOS) mRNA was significantly inhibited only by 5-CNA. On the other hand, LPS-induced nuclear translocation of p65 subunit of nuclear factor-κB was prevented only by amodiaquine. C-DIM12 increased nuclear localization of Nurr1 and transiently upregulated Nurr1 protein expression, whereas amodiaquine and 5-CNA had no effect on these parameters. Notably, inhibitory effect of 5-CNA on iNOS mRNA upregulation was reversed by co-application of amodiaquine. Conversely, inhibitory effect of amodiaquine on p65 nuclear translocation was cancelled by 5-CNA. These results reveal distinct characteristics of anti-inflammatory actions of Nurr1 ligands.

Keywords: inflammatory cytokine; microglia; nuclear factor kappa B; nuclear receptor.

MeSH terms

  • Amodiaquine* / pharmacology
  • Animals
  • Anti-Inflammatory Agents* / pharmacology
  • Cell Line
  • Indoles* / pharmacology
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Ligands
  • Lipopolysaccharides* / pharmacology
  • Mice
  • Microglia* / drug effects
  • Microglia* / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II* / genetics
  • Nitric Oxide Synthase Type II* / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 2* / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2* / metabolism
  • RNA, Messenger / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Lipopolysaccharides
  • Nr4a2 protein, mouse
  • Nitric Oxide Synthase Type II
  • Amodiaquine
  • Anti-Inflammatory Agents
  • Indoles
  • 1,1-bis(3'-indolyl)-1-(4-chlorophenyl)methane
  • Interleukin-1beta
  • Ligands
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Nos2 protein, mouse
  • NF-kappa B
  • RNA, Messenger