TRPA1 activation by cinnamaldehyde as target engagement biomarker: unraveling the involvement of secondary mediators
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1
Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
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2
Leuven Center for Algology, Department of Cardiovascular Sciences, KU Leuven, Belgium
Background: Transient receptor potential ankyrin 1 (TRPA1), an emerging target for pain therapy, is activated by cinnamaldehyde
(CA) and results in a reproducible increase in dermal blood flow (DBF) after local CA application (1). This study investigates the
mediators involved in this response in healthy volunteers.
Methods: Part I: Randomized, 2-way cross-over study using aspirin (1g, non-selective, irreversible COX-inhibitor) and aprepitant
(375mg, NK1-antagonist). Part II: randomized, 3-way cross-over study using aspirin, indomethacin (100mg, non-selective,
reversible COX-inhibitor) and celecoxib (400mg, reversible COX2-inhibitor). During all visits (separated by a wash-out of 14
days) drugs were administered orally. CA (2µl/20µl) was applied topically on the volar surface of the forearms during screening
and subsequent study periods. DBF was assessed using laser Doppler imaging (LDI) at baseline and at fixed time points for 60
minutes after CA application. Data are expressed as Area Under the Curve (AUC) over a 60 minutes period (meanSEM perfusion
units, PU).
Results: CA induced a >100% increase in DBF in all volunteers (25.3781.884 PU*min). Aprepitant was unable to block the
CA-induced DBF (20.5321.664 PU*min) in contrast to aspirin (4.705580 PU*min), which almost completely blocked the DBF
response (p<0.01, ANOVA) as depicted in figure 1.
INSERT IMAGE 2
Conclusion: In healthy volunteers, vasodilating prostaglandins seem to play an important role in CA-induced DBF. In mice,
indomethacin was unable to block CA-induced DBF (2). It is hypothesized whether CA-induced DBF is species-specific (mice
versus human) or drug-specific (aspirin versus indomethacin)? Results from part II, available at the EUFEMED conference,
should answer this question!
References:
1. Buntinx L, Chang L, Amin A, Morlion B, de Hoon J. Development of an in vivo target-engagement biomarker for TRPA1
antagonists in humans. Br J Clin Pharmacol. 2016.
2. Aubdool AA, Kodji X, Abdul-Kader N, Heads R, Fernandes ES, Bevan S, et al. TRPA1 activation leads to neurogenic vasodilatation:
involvement of reactive oxygen nitrogen species in addition to CGRP and NO. Br J Pharmacol. 2016173(15):2419-33.
Keywords:
Neurogenic Inflammation,
biomarker,
NSAIDs,
TRPA1,
Cinnamaldehyde
Conference:
EUFEMED 2017, London, United Kingdom, 17 May - 19 May, 2017.
Presentation Type:
Poster
Topic:
EUFEMED 2017 CONFERENCE
Citation:
Buntinx
L,
Barroso
S,
Vandendriessche
J,
Chang
L,
Morlion
B and
De Hoon
J
(2019). TRPA1 activation by cinnamaldehyde as target engagement biomarker: unraveling the involvement of secondary mediators.
Front. Pharmacol.
Conference Abstract:
EUFEMED 2017.
doi: 10.3389/conf.fphar.2017.62.00015
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Received:
29 Aug 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Dr. Linde Buntinx, Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium, linde.buntinx@uzleuven.be