In Altering the Release of Glucocorticoids, Ketorolac Exacerbates the Effects of Systemic Immune Stimuli on Expression of Proinflammatory Genes in the Brain

Abstract

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.

Omega-3 Fatty Acid Ethyl-Eicosapentaenoate Attenuates IL-1β-Induced Changes in Dopamine and Metabolites in the Shell of the Nucleus Accumbens: Involved with PLA2 Activity and Corticosterone Secretion

“…EPA effects of IL-1-induced changes in DA and PLA2 C Song et al neurotransmitters and metabolites was significantly changed, and IL-1-induced mRNA expressions related to PGE2, glucocorticoids and inflammation in the brain also occurred) (Song et al, 1999;Blais et al, 2002;Zhang and Rivest, 2000). Following decapitation, blood was collected and serum samples were used to measure corticosterone concentrations.…”

MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

“…Systemic administration of COX inhibitors indomethacin, ketoralac or NS-398 prior to LPS or IL1b challenges abrogates these responses. 11,37-40 COX inhibition prevents activation of PVN neurons and its afferent pathways in response to proinflammatory cytokines and LPS, 41,42 while intracerebral administration of PGE 2 stimulates these neuronal circuits and plasma ACTH and corticosterone release. [43][44][45] Moreover, both COX-2 and mPGES-1 are rapidly upregulated by circulating immune ligands 4,5,14,15,20,22,23,46 and COX-2-and mPGES-1-deficient mice do not develop fever in response to circulating LPS.…”

Delayed but Not Early Glucocorticoid Treatment Protects the Host during Experimental Herpes Simplex Virus Encephalitis in Mice

“…However, DEX is able to repress lipopolysaccharide (LPS)-induced NF-kB activation in the brain [22], and exogenous Cort can abolish stimulated IL-1b and TNF-a gene expression in microglial cells [23]. Recently, it was demonstrated that systemic pretreatment with endotoxin is able to abolish the strong and time-dependent transcriptional activation of inflammatory genes in microglial cells ipsilateral to the site of LPS intrastriatal injection.…”