title: Palmitoylethanolamide Regulates Production of Pro-Angiogenic Mediators in a Model of β Amyloid-Induced Astrogliosis In Vitro.
abstract: 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 (10-8-10-6M) 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.
authors: Mariateresa
authors: M
authors: Cipriano
authors: Giueseppe
authors: G
authors: Esposito
authors: Luana
authors: L
authors: Negro
authors: Elena
authors: E
authors: Capoccia
authors: Giovanni
authors: G
authors: Sarnelli
authors: Caterina
authors: C
authors: Scuderi
authors: Daniele
authors: D
authors: De Filippis
authors: Luca
authors: L
authors: Steardo
authors: Department of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy. iuvone@unina.it.
authors: Teresa
authors: T
authors: Iuvone
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D005911:Gliosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D004983:Ethanolamines; C449302:GW 6471; D018696:Neuroprotective Agents; D010080:Oxazoles; D047493:PPAR alpha; D010169:Palmitic Acids; D010446:Peptide Fragments; D064568:S100 Calcium Binding Protein beta Subunit; C579158:S100b protein, rat; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); D009569:Nitric Oxide; D014443:Tyrosine; C005958:palmidrol; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases