Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E2 synthesis in rat microglial cells

Fiebich, Bernd L.; Lieb, Klaus; Hüll, Michael; Aicher, Bernhard; Ryn, Joanne van; Pairet, M.; Engelhardt, G.

doi:10.1016/s0028-3908(00)00045-9

Cited by 93 publications

(76 citation statements)

References 49 publications

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“…It has been shown in several preparations that caffeine on its own does not inhibit tissue prostaglandin biosynthesis, nor does it augment inhibition exerted by COX inhibitors [e.g., [2][3][4]. However, results obtained in rat microglial cells suggest that adenosine A 2 receptor agonists can induce COX-2 mRNA and cause a concomitant increase in prostaglandin E 2 (PGE 2 ) biosynthesis [5]; in this preparation the nonselec-Ulcar/Schuligoi/Heinemann/Santner/ Amann tive adenosine receptor antagonist caffeine augmented the inhibitory effect of acetylsalicylic acid on endotoxininduced PGE 2 biosynthesis [6].…”

Section: Introductionmentioning

confidence: 91%

Inhibition of Prostaglandin Biosynthesis in Human Endotoxin-Stimulated Peripheral Blood Monocytes: Effects of Caffeine

Ulcar

Schuligoi²,

Heinemann³

et al. 2003

Pharmacology

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There is an ongoing debate about possible advantages of the coadministration of caffeine with cyclooxygenase (COX) inhibitors in the treatment of pain. There are results suggesting interference by caffeine with COX expression and activity in rat immune cells. In the present study, we have used, therefore, human endotoxin-stimulated monocytes to investigate a possible influence of caffeine on indometacin-induced inhibition of prostaglandin E₂ (PGE₂) formation. Endotoxin caused a concentration- and time-dependent increase in immunoreactive PGE₂ that was dependent on CD14-mediated mechanisms. In order to investigate pharmacological inhibition of the COX activity, a submaximal concentration of 1 ng/ml endotoxin (4 h exposure time) was used. Indometacin caused a concentration-dependent inhibition of PGE₂ with an apparent IC₅₀ of 8.9 ± 1.4 × 10^–9 mol/l and an I_max of 1 x 10^–7 mol/l. Caffeine (5 × 10^–6 to 1.5 × 10^–4 mol/l) on its own produced no statistically significant effect on endotoxin-induced PGE₂ formation. In the presence of caffeine (5 × 10^–6 to 1.5 × 10^–4 mol/l), inhibition of PGE₂ biosynthesis by indometacin (1 × 10^–8 mol/l) was not significantly altered. These results show that, in human monocytes, caffeine, up to concentrations severalfold higher than those reached in patients, has no significant effect on endotoxin-induced PGE₂ formation nor on its inhibition by indometacin.

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Section: Introductionmentioning

confidence: 91%

Inhibition of Prostaglandin Biosynthesis in Human Endotoxin-Stimulated Peripheral Blood Monocytes: Effects of Caffeine

Ulcar

Schuligoi²,

Heinemann³

et al. 2003

Pharmacology

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“…Therefore, it is diffi- cult to know whether acetaminophen truly has a greater ability to inhibit COX-3 than COX-1 or COX-2 or whether the IC 50 values merely reflect the variable activities of the Sf9 constructs, as previously speculated by David Aronoff at a COX-3 forum on the Internet (http://www.caymanchem.com/ app/template/cox3,Home.vm). It is also important to mention that the IC 50 values for acetaminophen in COX-3-transfected cells were 64 and 460 M in the presence of 5 and 30 M arachidonic acid, respectively (Chandrasekharan et al, 2002), whereas in other studies in endothelial cells (Boutaud et al, 2002;Kis et al, 2005), microglial cells (Fiebich et al, 2000;Greco et al, 2003), and in other cell types (for review, see Graham and Scott, 2005), the reported IC 50 values are several times lower. As also suggested by David Aronoff, using constructs with equivalent arachidonic acid utilization or purified preparations of the different COX isoforms exhibiting similar specific activities would allow a more useful comparison of the inhibitory potency of acetaminophen and NSAIDs against COX isoforms.…”

mentioning

confidence: 91%

Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties

Kis

Snipes²,

Busija³

2005

J Pharmacol Exp Ther

209

149

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Cyclooxygenase (COX)-3, a novel COX splice variant, was suggested as the key to unlocking the mystery of the mechanism of action of acetaminophen. Although COX-3 might have COX activity in canines, and this activity might be inhibited by acetaminophen, its low expression level and the kinetics indicate unlikely clinical relevance. In rodents and humans, COX-3 encodes proteins with completely different amino acid sequences than COX

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“…It has been reported to affect several microglial functions in vitro. In LPS-stimulated microglia, acetaminophen suppressed the synthesis of the inflammatory mediators PGE2, PGF2, and thromboxane B2 by inhibiting the activity of COX; however, it had no effect on the levels of the pro-inflammatory mediators TNF-α and NO [19,20] . Data in Figure 2A confirm these observations by showing that at therapeutic as well as supratherapeutic concentrations acetaminophen had no significant effect on NO released by LPS-stimulated BV-2 microglia.…”

Section: Resultsmentioning

confidence: 92%

“…Acetaminophen inhibits the synthesis of prostaglandin (PG) E2, PGF2, and thromboxane B2 by lipopolysaccharide (LPS)-stimulated microglia, yet has no effect on the levels of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and NO [19,20] . These effects are attributed to the inhibition of COX enzymatic activity, as the expression of the enzymes involved in PG synthesis, including COX, is not affected nor does the concentration of the PG precursor, arachidonic acid, significantly vary with acetaminophen treatment [20] .…”

Section: Introductionmentioning

confidence: 99%

Acetaminophen metabolites p-aminophenol and AM404 inhibit microglial activation

Slattery¹,

Klegeris²

2018

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Aim: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, deposits of amyloid beta and neurofibrillary tangles. Inflammation facilitated by microglia, the resident immune cells of the brain, contribute to the pathogenesis of AD. Epidemiological data indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), which are cyclooxygenase (COX) inhibitors, reduce the risk of developing AD when administered over the course of two or more years. The mechanisms underlying this protective effect are unknown. Acetaminophen (paracetamol), which is not effective as an inhibitor of COX in peripheral tissues, may provide similar protection without the adverse effects of chronic NSAID use. The beneficial effects of acetaminophen have been proposed to stem from its metabolites p-aminophenol and N-arachidonoylaminophenol (AM404), of which, AM404 possesses analgesic and antipyretic properties. The goal of this study was to compare the effects of acetaminophen and its metabolites on microglial immune function and to elucidate the molecular mechanisms engaged by these compounds.Methods: Lipopolysaccharide-stimulated BV-2 murine microglia were used as models. Microglial activation was monitored by their secretion of nitric oxide.Results: P-aminophenol and AM404 suppressed nitric oxide secretion from stimulated microglia more effectively than acetaminophen through pathways that were independent of COX inhibition, cannabinoid receptor type two (CB2) inhibition, and activation of transient receptor potential cation channel subfamily V member 1 (TRPV1). Conclusion:Since AM404 has been previously demonstrated to attenuate NF-kB activation, it is likely that the protective effects of acetaminophen against adverse microglia activation are mediated by its metabolites p-aminophenol and AM404 inhibiting this transcription factor.

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Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E2 synthesis in rat microglial cells

Cited by 93 publications

References 49 publications

Inhibition of Prostaglandin Biosynthesis in Human Endotoxin-Stimulated Peripheral Blood Monocytes: Effects of Caffeine

Inhibition of Prostaglandin Biosynthesis in Human Endotoxin-Stimulated Peripheral Blood Monocytes: Effects of Caffeine

Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties

Acetaminophen metabolites p-aminophenol and AM404 inhibit microglial activation

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