Stimulation of central ¦Â₂-adrenoceptors suppresses NF¦ÊB activity in rat brain: A role for I¦ÊB

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• 作者：Katie J. Ryan ; ¨¦adaoin Griffin ; Justin D. Yssel ; Karen M. Ryan ; Eoin N. McNamee ; Andrew Harkin ; Thomas J. Connor
• 关键词：¦Â2-Adrenoceptor ; Clenbuterol ; Formoterol ; NF¦ÊB ; I¦ÊB¦Á ; Neuroinflammation ; LPS ; Brain
• 刊名：Neurochemistry International
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：63
• 期：5
• 页码：368-378
• 全文大小：1471 K

文摘

In this study we examined the impact of systemic treatment with the long-acting brain penetrant ¦Â₂-adrenoceptor agonist clenbuterol on NF¦ÊB activity and I¦ÊB expression in rat brain. Clenbuterol decreased NF¦ÊB activity (p65 DNA binding) in nuclear extracts prepared from rat cortex and hippocampus for up to 8 h following a single treatment. This was accompanied by increased expression of I¦ÊB¦Á mRNA and protein. The temporal increase in I¦ÊB protein expression paralleled the suppression of NF¦ÊB activity, suggesting that I¦ÊB¦Á mediates the suppression NF¦ÊB activity observed. These actions of clenbuterol were prevented by pre-treatment with the non-selective ¦Â-adrenoceptor antagonist propranolol, the ¦Â₂-adrenoceptor antagonist ICI-118,551, but not the ¦Â₁-adrenoceptor antagonist metoprolol, suggesting that the effects of clenbuterol on I¦ÊB¦Á expression and NF¦ÊB activity are mediated specifically by the ¦Â₂-adrenoceptor. In addition, the actions of clenbuterol were mimicked by systemic administration of another highly selective long-acting ¦Â₂-adrenoceptor agonist formoterol. As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NF¦ÊB activation that occurs in response to an inflammatory stimulus. In this regard we demonstrate that clenbuterol inhibited I¦ÊB phosphorylation and I¦ÊB degradation and inhibited NF¦ÊB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide (LPS). In tandem, clenbuterol blocked expression of the NF¦ÊB-inducible genes TNF-¦Á and ICAM-1 following LPS administration. Our finding that clenbuterol and formoterol inhibit NF¦ÊB activity in the CNS further supports the idea that ¦Â₂-adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation-related neurodegeneration.