title: Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration.
abstract: Evidence indicates that the monoamine neurotransmitter noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and consequently may play a neuroprotective role where inflammatory events contribute to CNS pathology. Here we examined the ability of pharmacologically enhancing central noradrenergic tone to induce expression of anti-inflammatory cytokines in rat brain. Administration of the noradrenaline reuptake inhibitor reboxetine (15mg/kg; ip) combined with the alpha(2)-adrenoceptor antagonist idazoxan (1mg/kg; ip) induced interleukin-10 (IL-10) expression in rat cortex and hippocampus. In addition, these drug treatments induced IL-10 signaling as indicated by increased STAT3 phosphorylation and suppressor of cytokine signaling-3 (SOCS-3) mRNA expression. In contrast to the profound increase in IL-10 induced by the reboxetine/idazoxan combination, the other two broad spectrum anti-inflammatory cytokines IL-4 and TGF-beta were not induced by this treatment. The ability of combined treatment with reboxetine and idazoxan to induce IL-10 and SOCS3 expression was mediated by beta-adrenoceptor activation, as their induction was blocked by pre-treatment with the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced a time- and dose-dependent increase in central IL-10 and SOCS3 expression, and the ability of clenbuterol to induce IL-10 and SOCS-3 expression was blocked by the centrally acting beta-adrenoceptor antagonist, propranolol, and was mimicked by the highly selective beta(2)-adrenoceptor agonist formoterol. In all, these data indicate that increasing central noradrenergic tone induces IL-10 production and signaling in the CNS, which may protect against neurodegeneration.
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Eoin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ryan
authors.forename: Eadaoin W
authors.initials: EW
authors.lastname: Griffin
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: González-Reyes
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ryan
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002540:Cerebral Cortex / Q000276:immunology; D002976:Clenbuterol / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006624:Hippocampus / Q000276:immunology; D019329:Idazoxan / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009638:Norepinephrine / Q000276:immunology* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011433:Propranolol / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D011943:Receptors, Adrenergic, beta / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D009025:Morpholines; D011943:Receptors, Adrenergic, beta; D018343:Receptors, Adrenergic, beta-2; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D000077593:Reboxetine; D011433:Propranolol; D009638:Norepinephrine; D002976:Clenbuterol; D019329:Idazoxan