Effects of the inhibition of cyclo-oxygenase 1 or 2 or 5-lipoxygenase on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1beta in the male Rat.
The limited entry of interleukin-1beta (IL-1beta) into the central nervous system has led to the hypothesis that IL-1beta acts, through IL-1beta receptors located notably on endothelial cells, on the release of prostaglandins which in turn stimulate the hypothalamic-pituitary-adrenal (HPA) axis. We used cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors, before the injection of IL-1beta, to explore the role of arachidonic acid metabolic pathways on HPA axis activation. Adult male rats were i.m injected 20 min before i.p injection of IL-1beta, with (i): a COX-1/COX-2 inhibitor (ketoprofen); (ii) a COX-2 selective inhibitor (NS 398); or (iii) a 5-LOX inhibitor (BW A4C). Following this, rats were killed 90 min after i.p. IL-1beta injection and analysis for plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations and determination of anterior pituitary pro-opio melanocortin (POMC) gene transcription was conducted. Administration of the COX-1/COX-2 inhibitor led to a complete blockage of ACTH and corticosterone secretion and POMC gene transcription. The COX-2 inhibitor led to a complete blockade of ACTH secretion and POMC gene transcription but had no effect on corticosterone secretion. The 5-LOX inhibitor had no significant effect on any parameter. These results demonstrate the crucial role of eicosanoid pathways in mediating the stimulation of the HPA axis induced by IL-1beta. Moreover, we found a clear dissociation of the effect of the blockage of COXs upon ACTH and corticosterone secretion, suggesting that IL-1beta may act at the brain as well as at the adrenal cortex to stimulate the secretion of corticosterone.
Parsadaniantz
S M
SM
Laboratoire de Neurobiologie Cellulaire et Moléculaire, Faculté de Pharmacie, Paris, France. parsadan@st-antoine.inserm.fr
Lebeau
A
A
Duval
P
P
Grimaldi
B
B
Terlain
B
B
Kerdelhué
B
B
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D044482:Benzeneacetamides; D003345:Corticosterone / Q000097:blood; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007660:Ketoprofen / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology
D044482:Benzeneacetamides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006877:Hydroxamic Acids; D007375:Interleukin-1; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D012333:RNA, Messenger; D013449:Sulfonamides; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D003345:Corticosterone