Corticosterone primes the neuroinflammatory response to Gulf War Illness-relevant organophosphates independently of acetylcholinesterase inhibition

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting veterans of the 1991 Gulf War. Among the symptoms of GWI are those associated with sickness behaviour, observations suggestive of underlying neuroinflammation. The authors have shown that exposure of mice to the stress hormone, corticosterone (CORT), and to diisopropyl fluorophosphate (DFP), as a nerve agent mimic, results in marked neuroinflammation, findings consistent with a stress/neuroimmune basis of GWI. This study examined the contribution of irreversible and reversible acetylcholinesterase (AChE) inhibitors to neuroinflammation in our mouse model of GWI. Male C57BL/6J mice received four days of CORT (400 mg/L) in the drinking water followed by a single dose of chlorpyrifos (CPO; 8 mg/kg, i.p.), DFP (4 mg/kg, i.p.), pyridostigmine (PB; 3 mg/kg, i.p.), or physostigmine (PHY; 0.5 mg/kg, i.p.). CPO and DFP alone caused cortical and hippocampal neuroinflammation assessed by qPCR of TNF-?, IL-6, C-C chemokine ligand 2 (CCL2), IL-1?, leukaemia inhibitory factor (LIF) and oncostatin M (OSM); CORT pretreatment markedly augmented these effects. Additionally, CORT exposure prior to DFP or CPO enhanced activation of the neuroinflammation signal transducer, STAT3. In contrast, PHY or PB alone or with CORT pretreatment did not produce neuroinflammation or STAT3 activation. While all of the CNS-acting AChE inhibitors (DFP, CPO, and PHY) decreased brain AChE activity, CORT pretreatment abrogated these effects for the irreversible inhibitors. Taken together, these findings suggest that irreversible AChE inhibitor-induced neuroinflammation and particularly its exacerbation by CORT, result from non-cholinergic effects of these compounds, pointing potentially to organophosphorylation of other neuroimmune targets.

Authors: Locker AR, Michalovicz LT, Kelly KA, Miller JV, Miller DB, O’Callaghan JP. ;Full Source: Journal of Neurochemistry. 2017 May 13. doi: 10.1111/jnc.14071. [Epub ahead of print] ;