CCL3/macrophage inflammatory protein-1alpha induces fever and increases prostaglandin E2 in cerebrospinal fluid of rats: effect of antipyretic drugs.
The aim of this study was to investigate whether the increase in body temperature caused by intracerebroventricular (i.c.v.) injection of recombinant mouse CCL3/MIP1alpha [C-C (two adjacent conserved cysteines) ligand 3/macrophage inflammatory protein-1alpha] constitutes solely a hyperthermic response or a true integrated fever. Additionally, we examined the effects of systemic administration of different antipyretic drugs including the glucocorticoid dexamethasone, on cerebrospinal fluid (CSF) concentration of prostaglandin (PG) E2 and on febrile response induced by CCL3/MIP1alpha. I.c.v. administration of CCL3/MIP1alpha evokes an integrated fever accompanied by a reduction in tail skin temperature and an increase in PGE2 concentration in the CSF. Dexamethasone and indomethacin markedly reduced the fever and the elevation of CSF PGE2 concentration induced by lipopolysaccharide (LPS) whereas both response evoked by i.c.v. CCL3/MIP1alpha were insensitive to this steroid. Indomethacin only blocked the PGE2 increase in the CSF whereas ibuprofen and celecoxib each blocked the fever and the elevation of CSF PGE2. In this study, we have demonstrated for the first time that CCL3/MIP1alpha evokes an integrated febrile response accompanied by an increase of PGE2 levels in the CSF. These events are dissociated, especially in animals treated with indomethacin. If PGE2 does not participate in the febrile response evoked by CCL3/MIP1alpha, the inhibition of this response by celecoxib and ibuprofen indicates additional mechanisms to the well-known inhibition of COX enzymes by these drugs. Such mechanisms do not seem to depend on cytokine synthesis and subsequent COX-2 induction.
Soares
Denis Melo
DM
Laboratory of Pharmacology, Faculty of Pharmaceutical Science, Universidade de São Paulo, Ribeirão Preto, SP, Brazil, and Research Unit, Laboratory for Clinical and Experimental Pharmacology, Valme University Hospital, Seville, Spain.
Hiratsuka Veiga-Souza
Fabiane
F
Fabrício
Aline Sueli Coelho
AS
Javier Miñano
Francisco
F
Petto Souza
Glória Emília
GE
D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003907:Dexamethasone / Q000008:administration & dosage; D015232:Dinoprostone / Q000134:cerebrospinal fluid*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control*; D007124:Immunoenzyme Techniques / Q000379:methods; D007213:Indomethacin / Q000008:administration & dosage; D007276:Injections, Intraventricular / Q000379:methods; D008070:Lipopolysaccharides / Q000008:administration & dosage; D019402:Macrophage Inflammatory Proteins; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D003907:Dexamethasone; D015232:Dinoprostone; D007213:Indomethacin