title: Stimulation of central β2-adrenoceptors suppresses NFκB activity in rat brain: a role for IκB.
abstract: In this study we examined the impact of systemic treatment with the long-acting brain penetrant β2-adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain. Clenbuterol decreased NFκB activity (p65 DNA binding) in nuclear extracts prepared from rat cortex and hippocampus for up to 8h following a single treatment. This was accompanied by increased expression of IκBα mRNA and protein. The temporal increase in IκB protein expression paralleled the suppression of NFκB activity, suggesting that IκBα mediates the suppression NFκB activity observed. These actions of clenbuterol were prevented by pre-treatment with the non-selective β-adrenoceptor antagonist propranolol, the β2-adrenoceptor antagonist ICI-118,551, but not the β1-adrenoceptor antagonist metoprolol, suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the β2-adrenoceptor. In addition, the actions of clenbuterol were mimicked by systemic administration of another highly selective long-acting β2-adrenoceptor agonist formoterol. As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus. In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide (LPS). In tandem, clenbuterol blocked expression of the NFκB-inducible genes TNF-α and ICAM-1 following LPS administration. Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that β2-adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation-related neurodegeneration.
authors.affiliation: Neuroimmunology Research Group, Trinity College Institute of Neuroscience, Department of Physiology & School of Medicine, Trinity College, Dublin 2, Ireland.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ryan
authors.forename: Éadaoin
authors.initials: É
authors.lastname: Griffin
authors.forename: Justin D
authors.initials: JD
authors.lastname: Yssel
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ryan
authors.forename: Eoin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002976:Clenbuterol / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D051550:I-kappa B Kinase; D002976:Clenbuterol
keywords: Brain; Clenbuterol; Formoterol; IκBα; LPS; NFκB; Neuroinflammation; β(2)-Adrenoceptor