title: Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats.
abstract: BACKGROUND
  The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile.
  
  
  METHODS
  We tested whether oleoylethanolamide/palmitoylethanolamide (10 mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5 mg/kg, i.p.) in rats.
  
  
  RESULTS
  Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2(-)) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1β, cyclooxygenase-2, and prostaglandin E2, and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test.
  
  
  CONCLUSIONS
  Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinflammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinflammatory component.
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: Aline
authors.initials: A
authors.lastname: Sayd
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: María
authors.initials: M
authors.lastname: Antón
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: Francisco
authors.initials: F
authors.lastname: Alén
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: Javier Rubén
authors.initials: JR
authors.lastname: Caso
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: Javier
authors.initials: J
authors.lastname: Pavón
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Leza
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca).
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca). lorio@psi.ucm.es bgbueno@med.ucm.es.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.affiliation: Department of Psychobiology, Faculty of Psychology, Complutense University, Complutense University of Madrid (UCM), Madrid, Spain (Ms Antón, and Drs Alén, Rodríguez de Fonseca and Orio); Department of Pharmacology, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)), Madrid, Spain (Ms Sayd, and Drs Leza and García-Bueno); Department of Psychiatry, Faculty of Medicine, UCM, and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain (Dr Caso); UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga-Universidad de Málaga, and Red de Trastornos Adictivos, Málaga, Spain (Drs Pavón and Rodríguez de Fonseca). lorio@psi.ucm.es bgbueno@med.ucm.es.
authors.forename: Laura
authors.initials: L
authors.lastname: Orio
mesh_terms: D000577:Amides; D059445:Anhedonia / Q000187:drug effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D063388:Endocannabinoids / Q000008:administration & dosage*; D004731:Endotoxins; D004983:Ethanolamines / Q000008:administration & dosage; D005518:Food Preferences; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009829:Oleic Acids / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D010169:Palmitic Acids / Q000008:administration & dosage; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017208:Rats, Wistar; D055697:Taste Perception / Q000187:drug effects
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D063388:Endocannabinoids; D004731:Endotoxins; D004983:Ethanolamines; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D009829:Oleic Acids; D010169:Palmitic Acids; C488250:oleoylethanolamide; C044101:endotoxin, Escherichia coli; C005958:palmidrol; D003345:Corticosterone
keywords: OEA; PEA; anhedonia; lipopolysaccharide; neuroinflammation