Ladostigil Reduces the Adenoside Triphosphate/Lipopolysaccharide-Induced Secretion of Pro-Inflammatory Cytokines from Microglia and Modulate-Immune Regulators, TNFAIP3, and EGR1

Fanny Reichert, Keren Zohar, Elyad Lezmi, Tsiona Eliyahu, Shlomo Rotshenker, Michal Linial, Marta Weinstock*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Treatment of aging rats for 6 months with ladostigil (1 mg/kg/day) prevented a decline in recognition and spatial memory and suppressed the overexpression of gene-encoding pro-inflammatory cytokines, TNFα, IL1β, and IL6 in the brain and microglial cultures. Primary cultures of mouse microglia stimulated by lipopolysaccharides (LPS, 0.75 µg/mL) and benzoyl ATPs (BzATP) were used to determine the concentration of ladostigil that reduces the secretion of these cytokine proteins. Ladostigil (1 × 10−11 M), a concentration compatible with the blood of aging rats in, prevented memory decline and reduced secretion of IL1β and IL6 by ≈50%. RNA sequencing analysis showed that BzATP/LPS upregulated 25 genes, including early-growth response protein 1, (Egr1) which increased in the brain of subjects with neurodegenerative diseases. Ladostigil significantly decreased Egr1 gene expression and levels of the protein in the nucleus and increased TNF alpha-induced protein 3 (TNFaIP3), which suppresses cytokine release, in the microglial cytoplasm. Restoration of the aberrant signaling of these proteins in ATP/LPS-activated microglia in vivo might explain the prevention by ladostigil of the morphological and inflammatory changes in the brain of aging rats.

Original languageAmerican English
Article number112
JournalBiomolecules
Volume14
Issue number1
DOIs
StatePublished - 16 Jan 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Keywords

  • NFκB
  • NLRP3 inflammasome
  • P2x7 receptor
  • RNA-seq
  • aging rats
  • primary murine microglia

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