Premium
Corticosterone primes the neuroinflammatory response to Gulf War Illness‐relevant organophosphates independently of acetylcholinesterase inhibition
Author(s) -
Locker Alicia R.,
Michalovicz Lindsay T.,
Kelly Kimberly A.,
Miller Julie V.,
Miller Diane B.,
O'Callaghan James P.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14071
Subject(s) - neuroinflammation , acetylcholinesterase , pyridostigmine bromide , chemistry , endocrinology , diisopropyl fluorophosphate , medicine , pharmacology , corticosterone , pyridostigmine , hormone , biochemistry , inflammation , myasthenia gravis , enzyme
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 behavior, observations suggestive of underlying neuroinflammation. We 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 . Here, we examined the contribution of irreversible and reversible acetylcholinesterase ( AC hE) inhibitors to neuroinflammation in our mouse model of GWI . Male C57 BL /6J mice received 4 days of CORT (400 mg/L) in the drinking water followed by a single dose of chlorpyrifos oxon ( CPO ; 8 mg/kg, i.p.), DFP (4 mg/kg, i.p.), pyridostigmine bromide (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 tumor necrosis factor‐alpha, IL ‐6, C–C chemokine ligand 2, IL ‐1β, leukemia inhibitory factor and oncostatin M; CORT pretreatment markedly augmented these effects. Additionally, CORT exposure prior to DFP or CPO enhanced activation of the neuroinflammation signal transducer, signal transducer and activator of transcription 3 (STAT3). In contrast, PHY or PB alone or with CORT pretreatment did not produce neuroinflammation or STAT3 activation. While all of the CNS ‐acting AC hE inhibitors ( DFP , CPO , and PHY ) decreased brain AC hE activity, CORT pretreatment abrogated these effects for the irreversible inhibitors. Taken together, these findings suggest that irreversible AC hE 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.