title: Palmitoylethanolamide protects dentate gyrus granule cells via peroxisome proliferator-activated receptor-α.
abstract: Endocannabinoids like 2-arachidonoylglycerol strongly modulate the complex machinery of secondary neuronal damage and are shown to improve neuronal survival after excitotoxic lesion. Palmitoylethanolamide (PEA), the naturally occurring fatty acid amide of ethanolamine and palmitic acid, is an endogenous lipid known to mimic several effects of endocannabinoids even without binding to cannabinoid receptors. Here we show that PEA (0.001-1 μM) and the synthetic peroxisome proliferator-activated receptor (PPAR)-alpha agonist 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (Wy-14,643; 0.1-1 μM) reduced the number of microglial cells and protected dentate gyrus granule cells in excitotoxically lesioned organotypic hippocampal slice cultures (OHSCs). Treatment with the PPAR-alpha antagonist N-((2S)-2-(((1Z)-1-Methyl-3-oxo-3-(4-(trifluoromethyl)phenyl)prop-1-enyl)amino)-3-(4-(2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy)phenyl)propyl)propanamide (GW6471; 0.05-5 μM) blocked PEA-mediated neuroprotection and reduction of microglial cell numbers whereas the PPAR-gamma antagonist 2-chloro-5-nitro-N-phenyl-benzamide (GW9662; 0.01-1 μM) showed no effects. Immunocytochemistry and Western blot analyses revealed a strong PPAR-alpha immunoreaction in BV-2 microglial cells and in HT22 hippocampal cells. Intensity and location of PPAR-alpha immunoreaction remained constant during stimulation with PEA (0.01 μM; 1-36 h). In conclusion our data provide evidence that (1) PEA counteracted excitotoxically induced secondary neuronal damage of dentate gyrus granule cells, (2) PPAR-alpha but not PPAR-gamma is the endogenous binding site for PEA-mediated neuroprotection, and (3) PEA may activate PPAR-alpha in microglial cells and hippocampal neurons to exert its neuroprotective effects. In addition to classical endocannabinoids, PEA-mediated PPAR-alpha activation represents a possible target for therapeutic interventions to mitigate symptoms of secondary neuronal damage.
authors.affiliation: Dr. Senckenbergische Anatomie, Institut für Anatomie II, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Koch
authors.forename: Susanne
authors.initials: S
authors.lastname: Kreutz
authors.forename: Charlotte
authors.initials: C
authors.lastname: Böttger
authors.forename: Alexander
authors.initials: A
authors.lastname: Benz
authors.forename: Erik
authors.initials: E
authors.lastname: Maronde
authors.forename: Chalid
authors.initials: C
authors.lastname: Ghadban
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
authors.forename: Faramarz
authors.initials: F
authors.lastname: Dehghani
mesh_terms: D000577:Amides; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D063388:Endocannabinoids; D004983:Ethanolamines; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047493:PPAR alpha / Q000378:metabolism*; D010169:Palmitic Acids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000577:Amides; D063388:Endocannabinoids; D004983:Ethanolamines; D018696:Neuroprotective Agents; D047493:PPAR alpha; D010169:Palmitic Acids; C005958:palmidrol