In altering the release of glucocorticoids, ketorolac exacerbates the effects of systemic immune stimuli on expression of proinflammatory genes in the brain.
Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for their antiinflammatory, antipyretic, and analgesic properties. The molecular basis for the therapeutic action of NSAIDs is believed to be in their ability to inhibit cyclooxygenase (COX) activity and thereby blocking the production of prostaglandins. Emerging evidence now suggests that NSAIDs can exert their pharmacological effects through other mechanisms. This study investigated the influence of a nonselective COX-inhibitor ketorolac on IL-1beta- and TNFalpha-induced expression of proinflammatory genes in the brain. Systemic injection of both cytokines caused a rapid and transient transcriptional activation of COX-2 gene within the cerebral microvasculature, which was significantly enhanced by ketorolac. Expression of genes encoding the index of nuclear factor kappaB activity and the chemokine monocyte chemoattractant protein-1 was also increased by the NSAID. We speculated here that such effect was indirectly mediated via an altered secretion of plasma glucocorticoids because ketorolac is a potent inhibitor of the hypothalamic-pituitary-adrenal axis during systemic inflammation. As expected, pretreatment with the glucocorticoid receptor antagonist RU-486 exacerbated the influence of systemic immune stimuli on proinflammatory signaling. In contrast, exogenous corticosterone abolished the effects of ketorolac on IL-1beta-induced COX-2 and monocyte chemoattractant protein-1 gene expression in the cerebral endothelium. This drug plays therefore a paradoxical role in its ability to inhibit the circulating levels of glucocorticoids that are essential inhibitory feedback on the proinflammatory signal transduction pathways and gene transcription. In altering the production of key prostaglandins that are involved in the control of hypothalamic-pituitary-adrenal axis, ketorolac may have proinflammatory properties in the central nervous system during systemic immune stimuli.
Blais
Véronique
V
Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center and Department of Anatomy and Physiology, Laval University, Québec, Canada G1V 4G2.
Zhang
Ji
J
Rivest
Serge
S
D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics; D003345:Corticosterone / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D005246:Feedback; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects; D020672:I-kappa B Proteins / Q000235:genetics; D007109:Immunity / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics*; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D020910:Ketorolac / Q000009:adverse effects*; D008297:Male; D008833:Microcirculation / Q000378:metabolism; D015735:Mifepristone / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D010902:Pituitary Gland / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018932:Chemokine CCL2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D015735:Mifepristone; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D003345:Corticosterone; D020910:Ketorolac