title: The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro- and anti-inflammatory genes in the rat brain.
abstract: The functional significance for activation of inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), nuclear factor (NF)κB or NF-interleukin (IL)6 and their contribution to the induction of brain controlled sickness responses, such as fever, during infection and inflammation is unknown. Using AG490, previously shown to inhibit the STAT3- and NF-IL6-signaling pathway, we therefore investigated the central involvement of these two signaling pathways in mediating sickness behavior, fever and accompanying brain inflammation induced by peripheral lipopolysaccharide (LPS)-stimulation. Rats pre-treated i.c.v. with AG490 1 h before the i.p. LPS-challenge (100 μg/kg) showed a modestly exaggerated fever, attenuated adipsia and almost unimpaired locomotor activity compared to LPS-controls receiving vehicle (i.c.v.). The LPS-induced anorexia was not altered and AG490 did not have any effect on rats receiving PBS (i.p.). We did observe effects of AG490 on STAT3-signaling at 4 h, while AG490-mediated changes in brain activity of inflammatory transcription factors at 8 h were not significant. Increased NF-IL6 and suppressor of cytokines 3 mRNA-expression in AG490/LPS-treated rats were indicative of a compensative activation at 24 h. Moreover, a significant decrease in hypothalamic anti-inflammatory IL-10-expression and an increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA-expression 8 h after LPS-injection was revealed in AG490 pre-treated animals compared to solvent-treated LPS-controls. In summary, we have shown a dissociation between the effects of central AG490 treatment on fever and components of sickness behavior, which appears to be related to reduced IL-10 and increased mPGES-expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior.
authors.affiliation: Department of Veterinary-Physiology and -Biochemistry, Justus-Liebig-University Giessen, Frankfurter Strasse 100, D-35392 Giessen, Hessen, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Damm
authors.forename: Lois May
authors.initials: LM
authors.lastname: Harden
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Gerstberger
authors.forename: Joachim
authors.initials: J
authors.lastname: Roth
authors.forename: Christoph
authors.initials: C
authors.lastname: Rummel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018836:Inflammation Mediators / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D007276:Injections, Intraventricular; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020032:Tyrphostins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D053612:Janus Kinases