Sayd, AlineAntón, MaríaAlén, FranciscoCaso, Javier RubénPavón, JavierLeza, Juan CarlosRodríguez de Fonseca, FernandoGarcía-Bueno, BorjaOrio, Laura2016-08-092016-08-092015-04Said A, Antón M, Alén F, Caso JR, Pavón J, Leza JC, et al. Systemic Administration of Oleoylethanolamide Protects from Neuroinflammation and Anhedonia Induced by LPS in Rats. Int J Neuropsychopharmacol. 2015; 18 (6). pyu111.1461-1457http://hdl.handle.net/10668/2337Comparative Study; Journal Article; Research Support, Non-U.S. Gov't;Erratium: http://ijnp.oxfordjournals.org/content/19/3/pyw004.longBACKGROUND 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.enOLEALipopolysaccharideNeuroinflammationAnhedoniaAntiinflamatoriosCorticosteronaCitocinasModelos de enfermedad en animalesEncefalitisEndocannabinoidesEndotoxinasEtanolaminasPEAPreferencias alimenticiasLóbulo frontalSistema hipotálamo-hipofisarioMediadores de la inflamaciónPeroxidación de lípidosFármacos neuroprotectoresÁcidos oleicosEstrés oxidativoÁcidos palmíticosSistema hipófiso-suprarrenalRatas wistarPercepción del gustoMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Inflammatory AgentsMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Behavior, AnimalMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Body Temperature RegulationMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::BrainMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Adrenal Cortex Hormones::Hydroxycorticosteroids::11-Hydroxycorticosteroids::CorticosteroneMedical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::CytokinesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal::Disease Models, AnimalMedical Subject Headings::Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::EncephalitisMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Neurotransmitter Agents::EndocannabinoidsMedical Subject Headings::Chemicals and Drugs::Biological Factors::Toxins, Biological::Bacterial Toxins::EndotoxinsMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Alcohols::Ethanol::EthanolaminesMedical Subject Headings::Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Feeding Behavior::Food PreferencesMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral Cortex::Frontal LobeMedical Subject Headings::Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Diencephalon::Hypothalamus::Hypothalamus, Middle::Hypothalamo-Hypophyseal SystemMedical Subject Headings::Chemicals and Drugs::Biological Factors::Inflammation MediatorsMedical Subject Headings::Phenomena and Processes::Metabolic Phenomena::Metabolism::Energy Metabolism::Oxidation-Reduction::Lipid PeroxidationMedical Subject Headings::Check Tags::MaleMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Protective Agents::Neuroprotective AgentsMedical Subject Headings::Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Monounsaturated::Oleic AcidsMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Physiological Processes::Stress, Physiological::Oxidative StressMedical Subject Headings::Chemicals and Drugs::Lipids::Fatty Acids::Palmitic AcidsMedical Subject Headings::Anatomy::Endocrine System::Endocrine Glands::Pituitary-Adrenal SystemMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, WistarMedical Subject Headings::Psychiatry and Psychology::Psychological Phenomena and Processes::Mental Processes::Perception::Taste PerceptionMedical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Neurologic Manifestations::Neurobehavioral Manifestations::Anhedoniaresearch article25548106open access10.1093/ijnp/pyu1111469-5111PMC4438549