Palmitoylethanolamide Regulates Production of Pro-Angiogenic Mediators in a Model of β Amyloid-Induced Astrogliosis In Vitro

CNS Neurol Disord Drug Targets. 2015;14(7):828-37. doi: 10.2174/1871527314666150317224155.


Aβ-induced astrogliosis can worsen the eziopathogenesis of Alzheimer disease (AD) by the release of proinflammatory and pro-oxidant mediators. Activated glial cells may release also pro-angiogenic molecules. The role of angiogenesis in AD is still controversial: although angiogenesis brings oxygen and nutrients to injured tissue, it may also exacerbate reactive gliosis. Moreover, by altering blood-brain barrier permeability pro-angiogenic mediators promote passage of inflammatory/immune-competent cells into the brain, thereby exacerbating gliosis. The release of proangiogenic factors during astrogliosis may thus be a key-step in controlling AD progression. The endogenous fatty acid amide, palmitoylethanolamide (PEA), is a pleiotropic mediator exerting anti-inflammatory, antinociceptive and antiangiogenic effects in several in vitro and in vivo models of chronic-degenerative disease. In this study, we investigated the effects of PEA in AD angiogenesis and neuroinflammation by using conditioned medium from untreated and Aβ-treated C6 rat astroglioma cells and HUVEC human endothelial cells. PEA (10-8-10-6 M) concentration-dependently reduced expression of pro-inflammatory and pro-angiogenic markers in Aβ (1 μg/mL)-stimulated C6 cells. Moreover, culture medium from PEA-treated C6 cells reduced HUVEC cell proliferation as compared to cells treated with conditioned medium from Aβ-treated C6 cells. Immunocytochemical analysis revealed that PEA treatment inhibited nuclear levels of mitogen-activated protein kinase 1 (the main pro-angiogenic pathway) and cytoplasmic vascular endothelial growth factor in HUVEC cells receiving C6 conditioned medium. Finally, the peroxisome proliferator-activated receptor alpha inhibitor GW6471, added to Aβ-treated C6 cells blocked all PEA effects in this model, suggesting that PEA acts through a proliferator-activated receptor alpha-dependent mechanism on astroglial cells. Collectively, these data support the potential therapeutic utility of PEA in AD.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amides
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Dose-Response Relationship, Drug
  • Ethanolamines / pharmacology*
  • Gliosis / drug therapy*
  • Gliosis / metabolism
  • Humans
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Oxazoles / pharmacology
  • PPAR alpha / antagonists & inhibitors
  • PPAR alpha / metabolism
  • Palmitic Acids / pharmacology*
  • Peptide Fragments / metabolism*
  • Rats
  • S100 Calcium Binding Protein beta Subunit / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / pharmacology
  • Vascular Endothelial Growth Factor A / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Amides
  • Amyloid beta-Peptides
  • Ethanolamines
  • GW 6471
  • Neuroprotective Agents
  • Oxazoles
  • PPAR alpha
  • Palmitic Acids
  • Peptide Fragments
  • S100 Calcium Binding Protein beta Subunit
  • S100b protein, rat
  • Vascular Endothelial Growth Factor A
  • amyloid beta-protein (1-42)
  • Nitric Oxide
  • Tyrosine
  • palmidrol
  • Adenosine Triphosphate
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • p38 Mitogen-Activated Protein Kinases