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.

β2-Adrenergic receptors in immunity and inflammation: Stressing NF-κB

“…In line with this, b 2 -AR agonists have been proposed as therapeutic intervention in sepsis (reviewed by de Montmollin et al, 2009) and neurodegenerative disorders (McNamee et al, 2010;Ryan et al, 2013).…”

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist

“…While we present some of the first evidence that anti-inflammatory effects of xamoterol may be ADRB1-mediated, we think that ADRB1 and ADRB2 both have anti-inflammatory actions as the anti-inflammatory effect of the non-selective full agonist, isoproterenol are only partially reversed by each of a selective ADRB1 or ADRB2 antagonist. Indeed others have reported on anti-inflammatory actions of ADRB2, and both receptors should be considered as therapeutic targets (Qian et al 2011; Ryan et al 2013). …”

Pharmacological targeting of β2‐adrenoceptors is neuroprotective in the LPS inflammatory rat model of Parkinson's disease

“…Previous reports have indicated that the endogenous catecholaminergic transmitter noradrenaline suppresses the inflammatory response and production of neurotoxic substances including TNF‐α, IL‐1β, and NO in the brain (Feinstein et al, ; McNamee, Ryan, Kilroy, & Connor, ; Ryan et al, ). Moreover, noradrenaline negatively regulates the IL‐1 system in glial cells via up‐regulation of IL‐1 receptor antagonist (IL‐1RA) and the IL‐1 receptor, Type ІІ decoy receptor in vitro (McNamee, Ryan, Kilroy, & Connor, ) and in vivo (McNamee, Griffin, Ryan, et al, ) and raises CNS expression of the broad‐spectrum anti‐inflammatory cytokine IL‐10 and its downstream signalling molecule suppressor of cytokine signalling 3 (McNamee, Ryan, Griffin, et al, ).…”

“…Pretreatment with clenbuterol attenuates expression of the pro‐inflammatory molecules IL‐1β, IFN‐γ, and inducible NOS in the kainic acid model of excitotoxicity (Gleeson et al, ) and suppresses NF‐κB activity and expression of the NF‐κB‐inducible genes TNF‐α and ICAM‐1 in response to bacterial LPS (i.c.v.) in rats, whilst concurrently elevating expression of the NF‐κB‐inhibitory protein IκBα (Ryan et al, ). Formoterol is a long‐acting, highly selective β 2 ‐adrenoceptor agonist which, in conjunction with the anti‐inflammatory corticosteroid budesonide, is in clinical use as an FDA‐approved metred dose inhaler for the treatment of asthma and airflow obstruction in patients with chronic obstructive pulmonary disease (Rosenhall et al, ).…”