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Cited by 22Inflammatory mediators and NSAID effectsNeuroinflammation and Neurodegeneration MechanismsStress Responses and Cortisol

In altering the release of glucocorticoids, ketorolac exacerbates the effects of systemic immune stimuli on expression of proinflammatory genes in the brain

Blais, Véronique, Zhang, Ji, Rivest, Serge·2002·Endocrinology
DOI 10.1210/en.2002-220598
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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.

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  • Non-selective COX inhibitors ketorolac and indomethacin potentiate the expression of NF-kappaB target genes in brain capillaries and parenchymal microglia during systemic inflammation by hampering activation of the HPA axis and subsequent release of GCs.

    “Complementarily, the non-selective COX inhibitors ketorolac and indomethacin were found to potentiate the expression of NF-κB target genes in brain capillaries and parenchymal microglia during systemic inflammation (i.v. bolus of LPS, IL-1β, or TNF-α) by hampering the activation of the HPA axis and the subsequent release of GCs.”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [135]

  • The effect of COX inhibitors on NF-kappaB target genes could be replicated by administration of the GR antagonist RU486.

    “Interestingly, this effect could be replicated by the administration of the GR antagonist RU486 (mifepristone) (135, 136).”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [135]

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Authors
Blais, V., Zhang, J., & Rivest, S.
Affiliations
Centre hospitalier de l'Université Laval (CA)
Corresponding author
Rivest, Serge
ORCID
Rivest, Serge
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2002-12
Volume
143
Issue
12
Pages
4820-4827
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2002-220598
OpenAlex
W2007925044
Cited by
22
References
24
Citations by year
2021: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2012: 1
FWCI
0.61
Type
journal article
Language
en
Open access
closed
Locations
  • Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Université Laval
Topics
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
ketorolac, nonsteroidal anti-inflammatory drugs, glucocorticoids, hypothalamic-pituitary-adrenal axis, pro-inflammatory gene expression, IL-1β, TNF-α, cyclooxygenase-2, MCP-1, NF-κB, cerebral microvasculature, corticosterone, RU486, systemic inflammation, neuroinflammation
MeSH terms
NF-KappaB Inhibitor alpha, Adrenal Glands, Animals, Brain, Corticosterone, Feedback, Glucocorticoids, Hypothalamus, Immunity, Inflammation, Interleukin-1, Isoenzymes, Male, Microcirculation, Pituitary Gland, Prostaglandin-Endoperoxide Synthases, Receptors, Glucocorticoid, RNA, Messenger, Tumor Necrosis Factor-alpha, Signal Transduction, Mifepristone, Gene Expression, Cyclooxygenase Inhibitors, Rats, Sprague-Dawley, Chemokine CCL2, I-kappa B Proteins, Ketorolac, Rats, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors

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