Ambrosin, a potent NF-κβ inhibitor, ameliorates lipopolysaccharide induced memory impairment, comparison to curcumin

PLoS One. 2019 Jul 5;14(7):e0219378. doi: 10.1371/journal.pone.0219378. eCollection 2019.

Abstract

Despite its poor bioavailability, curcumin is a promising natural polyphenol targeting NF-κβ. NF-κβ is a target for new therapeutics because it plays a pivotal role in the pathophysiology of Alzheimer disease (AD). In contrast, ambrsoin, a sesquiterpene lactone which is a potent NF-κβ inhibitor, is scarcely studied in AD models. The current work aims to assess the efficacy of ambrosin as a possible remedy for AD. In silico studies showed that bioavailability and BBB permeability could be favorable for ambrosin over curcumin. Memory impairment was induced in mice by single intraperitoneal injection of LPS (0.4 mg/kg). Treated groups received curcumin (100 mg/kg) or ambrosin at doses (5 or 10 mg/kg) for 7 days. Mice in treated groups showed a significant improvement in memory functions during Morris water maze and object recognition tests. Curcumin and ambrosin (10 mg/kg) inhibited the upsurge of NF-κβp65 transcript and protein levels. Consequently, downstream pro-inflammatory and nitrosative mediators were inhibited, namely, TNF-α, IL-1β, COX-2 and iNOS. BACE1 was inhibited, thereby reducing amyloid plaques (Aβ) deposition and eventually reducing inflammation and apoptosis of neurons as revealed by immunohistopathological examination. In conclusion, ambrosin can be repurposed as AD remedy after further pharmacokinetic/pharamacodynamic assessments. It could serve as an additional lead drug for AD therapeutics.

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apoptosis / drug effects
  • Biomarkers
  • Curcumin / chemistry
  • Curcumin / pharmacology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / adverse effects
  • Male
  • Maze Learning
  • Memory / drug effects*
  • Memory Disorders / drug therapy
  • Memory Disorders / etiology*
  • Memory Disorders / metabolism*
  • Memory Disorders / psychology
  • Mice
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / chemistry
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Sesquiterpenes, Guaiane / chemistry
  • Sesquiterpenes, Guaiane / pharmacology*
  • Signal Transduction / drug effects
  • Structure-Activity Relationship

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Plant Extracts
  • Sesquiterpenes, Guaiane
  • ambrosin
  • Curcumin

Grant support

The authors received no specific funding for this work.