Palmitoylethanolamide improves colon inflammation through an enteric glia/toll like receptor 4-dependent PPAR-α activation

Gut. 2014 Aug;63(8):1300-12. doi: 10.1136/gutjnl-2013-305005. Epub 2013 Sep 30.

Abstract

Objective: Enteric glia activation has been reported to amplify intestinal inflammation via the enteroglial-specific S100B protein. This neurotrophin promotes macrophage recruitment in the mucosa, amplify colonic inflammation and interacts with toll-like receptors (TLR). Molecules inhibiting S100B-driven enteric activation might mitigate the course of ulcerative colitis (UC). This study aims to investigate the effects of palmitoylethanolammide (PEA), a drug able to counteract astroglial activation in the central nervous system, on intestinal inflammation, in humans and mice.

Design: Mouse models of dextran sodium sulphate (DSS)-induced colitis, colonic biopsies deriving from UC patients and primary cultures of mouse and human enteric glial cells (EGC), have been used to assess the effects of PEA, alone or in the presence of specific PPARα or PPARγ antagonists, on: macroscopic signs of UC (DAI score, colon length, spleen weight, macrophages/neutrophils infiltration); the expression and release of proinflammatory markers typical of UC; TLR pathway in EGCs.

Results: PEA treatment improves all macroscopic signs of UC and decreases the expression and release of all the proinflammatory markers tested. PEA anti-inflammatory effects are mediated by the selective targeting of the S100B/TLR4 axis on ECG, causing a downstream inhibition of nuclear factor kappa B (NF-kB)-dependent inflammation. Antagonists at PPARα, but not PPARγ, abolished PEA effects, in mice and in humans.

Conclusions: Because of its lack of toxicity, its ability in reducing inflammation and its selective PPARα action, PEA might be an innovative molecule to broaden pharmacological strategies against UC.

Keywords: ENTERIC NERVOUS SYSTEM; GUT INFLAMMATION; NERVOUS CONTROL OF INTESTINAL FUNCTIONS; ULCERATIVE COLITIS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / drug therapy
  • Colitis / metabolism
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / metabolism
  • Colitis, Ulcerative / pathology*
  • Colon, Sigmoid / chemistry
  • Colon, Sigmoid / pathology
  • Cyclooxygenase 2 / metabolism
  • Dextran Sulfate
  • Dinoprostone / metabolism
  • Endocannabinoids / pharmacology
  • Endocannabinoids / therapeutic use*
  • Ethanolamines / pharmacology
  • Ethanolamines / therapeutic use*
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Indoles / pharmacology
  • Male
  • Mice
  • Middle Aged
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neuroglia / drug effects
  • Neuroglia / metabolism*
  • Neutrophil Infiltration / drug effects
  • Nitric Oxide / analysis
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • PPAR alpha / antagonists & inhibitors
  • PPAR alpha / metabolism*
  • PPAR gamma / antagonists & inhibitors
  • Palmitic Acids / pharmacology
  • Palmitic Acids / therapeutic use*
  • Rectum / chemistry
  • Rectum / pathology
  • S100 Calcium Binding Protein beta Subunit / metabolism*
  • Severity of Illness Index
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 2-chloro-5-nitrobenzanilide
  • Anilides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Endocannabinoids
  • Ethanolamines
  • Glial Fibrillary Acidic Protein
  • Indoles
  • NF-kappa B
  • Nerve Tissue Proteins
  • PPAR alpha
  • PPAR gamma
  • Palmitic Acids
  • S100 Calcium Binding Protein beta Subunit
  • S100B protein, human
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • glial fibrillary astrocytic protein, mouse
  • MK-886
  • Nitric Oxide
  • palmidrol
  • Dextran Sulfate
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • Dinoprostone