Nobiletin Protects against Systemic Inflammation-Stimulated Memory Impairment via MAPK and NF-κB Signaling Pathways

J Agric Food Chem. 2019 May 8;67(18):5122-5134. doi: 10.1021/acs.jafc.9b00133. Epub 2019 Apr 24.

Abstract

Neuroinflammation has been intensively demonstrated to be related to various neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). A natural polymethoxylated flavone, nobiletin (NOB) has been reported to alleviate oxidative stress, insulin resistance, and obesity. In this study, we evaluated the protection effects of NOB on neuroinflammation and memory deficit. Three-month mice were administrated with NOB by oral gavage every day for 6 weeks (100 mg/kg/day); subsequently mice were injected intraperitoneally with lipopolysaccharide (LPS) for 7 days. Results of behavioral tests revealed that NOB dramatically ameliorated LPS-triggered memory deficit regarding synaptic dysfunctions and neuronal loss. Also, NOB suppressed the microglial activation and proinflammatory cytokine secretion, such as COX-2, IL-1β, TNF-α, and iNOS. Similarly, upon LPS stimulation, pretreatment NOB diminished the secretion of the proinflammatory cytokines in BV-2 microglia cells by exposure to LPS via modulating MAPKs, PI3K/AKT, and NF-κB signaling pathways. In addition, NOB alleviated LPS-amplified redox imbalance, disturbance of mitochondrial membrane potential (MMP), and dampening of the expression of protein related to mitochondrial respiration. The present study provides compelling evidence that NOB decreased LPS-stimulated neuroinflammation and memory impairment through maintaining cellular oxidative balance and blocking the NF-κB transcriptional pathway, illustrating that the nutritional compound NOB may serve as a potential approach to alleviate neuroinflammation-related diseases.

Keywords: NF-κB/MAPKs/PI3K/Akt signaling pathways; lipopolysaccharide; memory impairment; mitochondrial function; neuroinflammation; nobiletin.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / immunology
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / immunology
  • Flavones / administration & dosage*
  • Humans
  • Inflammation / complications*
  • Inflammation / genetics
  • Inflammation / immunology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Male
  • Memory Disorders / etiology
  • Memory Disorders / genetics
  • Memory Disorders / immunology
  • Memory Disorders / prevention & control*
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / immunology
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / immunology*
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Flavones
  • Interleukin-1beta
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • nobiletin
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinase Kinases