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Evening primrose oil or forskolin ameliorates celecoxib-enhanced upregulation of tissue factor expression in mice subjected to lipopolysaccharide-induced endotoxemia

Abstract

Celecoxib, a selective cyclooxygenase-2 inhibitor, produces thrombotic events in patients predisposed to cardiovascular risk factors. One theory reported an increase in endothelial expression of tissue factor (TF) as a predisposing factor. This work explored the effect of evening primrose oil (EPO), a source of prostaglandin E1, and forskolin (a cyclic adenosine monophosphate stimulator) against the prothrombotic effect of celecoxib in mice. Lipopolysaccharide mouse model of endotoxemia was used to induce an upregulation of TF activity. Male mice received celecoxib (25 mg/kg), celecoxib plus EPO, or celecoxib plus forskolin for 4 weeks and then subjected to a prothrombotic challenge in the form of an intraperitoneal injection of lipopolysaccharide. Results showed an increase in plasma TF activity, endothelial TF expression, and thrombin–antithrombin (TAT) but lower antithrombin III (ATIII) level in mice that received celecoxib in comparison to those that received the vehicle. Adding EPO or forskolin to celecoxib regimen significantly decreased the prothrombotic effect of celecoxib. A positive correlation (r = 0.8501) was found between TF activity and TAT. Co-administration of EPO or forskolin decreased the activity of TF and mitigated the prothrombotic effect of celecoxib. Therefore, these combinations may have the utility to abrogate the prothrombotic adverse effect of celecoxib in clinical setting.

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Abbreviations

AC:

Adenylyl cyclase

cAMP:

Cyclic adenosine monophosphate

ATIII:

Antithrombin III

CMC:

Carboxymethyl cellulose

COX-2:

Cyclooxygenase-2

DMSO:

Dimethylsulfoxide

EPO:

Evening primrose oil

FSK:

Forskolin

GLA:

Gamma linolenic acid

LPS:

Lipopolysaccharide

PGE1:

Prostaglandin E1

TAT:

Thrombin–antithrombin

TF:

Tissue factor

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Acknowledgements

Authors thank Amoun Pharmaceutical Company for the generous gift of celecoxib. Authors wish to acknowledge Dr. Daniel Kirchhofer for kindly providing tissue factor antibody 1H1 and Dr. Lars Petersen for the generous gift of mouse factor VIIa.

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Correspondence to Sawsan A. Zaitone.

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Mosaad, S.M., Zaitone, S.A., Ahmed, A.A.M. et al. Evening primrose oil or forskolin ameliorates celecoxib-enhanced upregulation of tissue factor expression in mice subjected to lipopolysaccharide-induced endotoxemia. Naunyn-Schmiedeberg's Arch Pharmacol 390, 483–492 (2017). https://doi.org/10.1007/s00210-017-1342-y

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  • DOI: https://doi.org/10.1007/s00210-017-1342-y

Keywords

  • Celecoxib
  • Evening primrose oil
  • Forskolin
  • Lipopolysaccharide
  • Thrombosis
  • Tissue factor