The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: implications for a role of COX-1
Teeling, J.L., Cunningham, C., Newman, Tracey A. and Perry, V.H. (2010) The effect of non-steroidal anti-inflammatory agents on behavioural changes and cytokine production following systemic inflammation: implications for a role of COX-1. Brain, Behavior and Immunity, 24, (3), 409-419. (doi:10.1016/j.bbi.2009.11.006). (PMID:19931610).
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Systemic inflammation gives rise to metabolic and behavioural changes, largely mediated by pro-inflammatory cytokines and prostaglandin production (PGE(2)) at the blood-brain barrier. Despite numerous studies, the exact biological pathways that give rise to these changes remains elusive. This study investigated the mechanisms underlying immune-to-brain communication following systemic inflammation using various anti-inflammatory agents. Mice were pre-treated with selective cyclo-oxygenase (COX) inhibitors, thromboxane synthase inhibitors or dexamethasone, followed by intra-peritoneal injection of lipopolysaccharide (LPS). Changes in body temperature, open-field activity, and burrowing were assessed and mRNA and/or protein levels of inflammatory mediators measured in serum and brain. LPS-induced systemic inflammation resulted in behavioural changes and increased production of IL-6, IL-1beta and TNF-alpha, as well as PGE(2) in serum and brain. Indomethacin and ibuprofen reversed the effect of LPS on behaviour without changing peripheral or central IL-6, IL-1beta and TNF-alpha mRNA levels. In contrast, dexamethasone did not alter LPS-induced behavioural changes, despite complete inhibition of cytokine production. A selective COX-1 inhibitor, piroxicam, but not the selective COX-2 inhibitor, nimesulide, reversed the LPS-induced behavioural changes without affecting IL-6, IL-1beta and TNF-alpha protein expression levels in the periphery or mRNA levels in the hippocampus. Our results suggest that the acute LPS-induced changes in burrowing and open-field activity depend on COX-1. We further show that COX-1 is not responsible for the induction of brain IL-6, IL-1beta and TNF-alpha synthesis or LPS-induced hypothermia. Our results may have implications for novel therapeutic strategies to treat or prevent neurological diseases with an inflammatory component.
|Digital Object Identifier (DOI):||doi:10.1016/j.bbi.2009.11.006|
|Keywords:||cytokines, behaviour, systemic inflammation, indomethacin, COX-1, COX-2|
|Subjects:||R Medicine > RB Pathology
R Medicine > RC Internal medicine
|Divisions:||Faculty of Medicine > Clinical and Experimental Sciences
|Date Deposited:||17 May 2012 14:21|
|Last Modified:||14 Apr 2014 11:41|
Impact of systemic inflammation on cognition and the underlying mechanisms
Funded by: BBSRC (BBS/B/15864)
1 October 2004 to 31 January 2008
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