Noradrenaline acting at central beta-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: implications for neurodegeneration

Brain Behav Immun. 2010 May;24(4):660-71. doi: 10.1016/j.bbi.2010.02.005. Epub 2010 Mar 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / administration & dosage
  • Adrenergic Uptake Inhibitors / pharmacology
  • Adrenergic alpha-Antagonists / administration & dosage
  • Adrenergic alpha-Antagonists / pharmacology
  • Adrenergic beta-Agonists / administration & dosage
  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Antagonists
  • Animals
  • Brain / drug effects
  • Brain / immunology
  • Brain / metabolism*
  • Cerebral Cortex / immunology
  • Clenbuterol / administration & dosage
  • Clenbuterol / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Hippocampus / immunology
  • Idazoxan / administration & dosage
  • Idazoxan / pharmacology
  • Injections, Intraperitoneal
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism*
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Male
  • Morpholines / administration & dosage
  • Morpholines / pharmacology
  • Norepinephrine / immunology*
  • Norepinephrine / pharmacology
  • Phosphorylation / drug effects
  • Propranolol / administration & dosage
  • Propranolol / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reboxetine
  • Receptors, Adrenergic, beta / classification
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Receptors, Adrenergic, beta-2
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • Adrenergic Uptake Inhibitors
  • Adrenergic alpha-Antagonists
  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Morpholines
  • Receptors, Adrenergic, beta
  • Receptors, Adrenergic, beta-2
  • STAT3 Transcription Factor
  • Socs3 protein, rat
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-4
  • Reboxetine
  • Propranolol
  • Norepinephrine
  • Clenbuterol
  • Idazoxan