The involvement of TRPA1 channel activation in the inflammatory response evoked by topical application of cinnamaldehyde to mice

Silva, Cássia Regina; Oliveira, Sara Marchesan; Rossato, Mateus; Dalmolin, Gerusa Duarte; Guerra, Gustavo Petri; Prudente, Arthur Silveira; Cabrini, Daniela Almeida; Otuki, Michel Fleith; André, Eunice; Ferreira, Juliano

doi:10.1016/j.lfs.2011.03.017

Cited by 43 publications

(25 citation statements)

References 49 publications

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“…This gives the CA model an extra advantage as a targetengagement model in future clinical research. Moreover, there seems to be no desensitization of the CA response after repeated administration, which is in line with preclinical findings in mice [19]. Another unresolved question is whether the DBF response observed is due to activation of neuronal and/or vascular TRPA1.…”

Section: Figuresupporting

confidence: 82%

“…The inter-arm reproducibility ( Figure 2B) was completed in 10 healthy Caucasian volunteers, of which six were males. Mean ± SD (range) for age, BMI, systolic blood pressure, diastolic blood pressure and heart rate were 23 ± 2 (19)(20)(21)(22)(23)(24)(25) years, 21 ± 3 (19-25) kg m À2 , 119 ± 13 (99-138) mmHg, 73 ± 7 (63-82) mmHg and 76 ± 9 (63-93) bpm, respectively. There was no difference in DBF response to 10% CA between the right and left arms at 10 min (1087 ± 372 vs. 1009 ± 349%, P = 0.60), 20 min (1181 ± 405 vs. 1236 ± 363%, P = 0.80), 30 min (1084 ± 401 vs. 1135 ± 365%, P = 0.91), 40 min (921 ± 418 vs. 992 ± 414%, P = 0.44), and 50 min (642 ± 356 vs. 686 ± 346%, P = 0.26) (paired t-test).…”

Section: Resultsmentioning

confidence: 99%

“…Likewise, the topical application of CA caused a TRPA1-dependent acute inflammatory response characterized by oedema formation and leukocyte infiltration [19]. Aubdool et al showed that CGRP plays a key role in this murine TRPA1 activation, but also nitric oxide (NO) derived from neuronal nitric oxide synthase (nNOS) is involved [20].…”

Section: Introductionmentioning

confidence: 99%

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Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Buntinx

Chang

Amin

et al. 2016

Brit J Clinical Pharma

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AIMTo develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers. METHODSDose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI). RESULTSAll three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC 0-50min of 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC 0-50min , CCC = 0.91) and visits (AUC 0-50min , CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power. CONCLUSIONSEvaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cinnamaldehyde, the main component of cinnamon, activates the TRPA1 receptor and induces vasodilatation when applied on the human skin.• TRPA1, a non-selective cation channel, is expressed in small diameter nociceptors and involved in persistent to chronic painful states such as inflammation, neuropathic pain and migraine.• TRPA1 is an emerging target for treating these and other neurogenic inflammatory conditions. WHAT THIS STUDY ADDS• Cinnamaldehyde 10% topical solution is tolerable and safe to use in healthy volunteers.• Cinnamaldehyde 10% applied on the human skin induces a robust increase in dermal blood flow which can be measured with laser Doppler imaging and is reproducible over time and between arms. • The cinnamaldehyde model can be used in future early clinical development studies with TRPA1 antagonists as a target engagement biomarker to guide dose selections for efficacy studies. Tables of Links

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Section: Figuresupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

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Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Buntinx

Chang

Amin

et al. 2016

Brit J Clinical Pharma

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“…CA works by sensitizing the thermo-receptive and inflammation-facilitatory ion-channel TRPA1. 57 Topical application of 10% CA has previously been shown to cause mild to moderate pain, mechanical and thermal hyperalgesia and neurogenic inflammation in human skin and rodents. 23,40,43,66 At lower concentrations, topical CA has been found to evoke itch in rodents and also in humans.…”

Section: Introductionmentioning

confidence: 99%

High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde

Andersen

Gazerani

Arendt-Nielsen

2016

The Journal of Pain

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Drugs interacting with transient receptor potential channels are of great therapeutic potential. In the present study we established cutaneous pain and hyperalgesia using the TRPA1 agonist CA. Subsequently, we showed that the frequently used topical counterirritant and TRPM8 agonist, L-menthol, decreased evoked pain, hyperalgesia, and inflammation, indicating direct and indirect antinociceptive mechanisms.

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“…Ear thickness was measured before and after induction of the inflammatory response using a digital micrometer (Starret Series 734, Portland, OR) 23 . The micrometer was applied near the tip of the ear just distal to the cartilaginous ridges.…”

Section: Ear Edema Measurementmentioning

confidence: 99%

In vitro and in vivo evaluation of a desonide gel-cream photostabilized with benzophenone-3

Rosa

Santos²,

Lehmen³

et al. 2015

Drug Development and Industrial Pharmacy

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The involvement of TRPA1 channel activation in the inflammatory response evoked by topical application of cinnamaldehyde to mice

Cited by 43 publications

References 49 publications

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans

High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde

In vitro and in vivo evaluation of a desonide gel-cream photostabilized with benzophenone-3

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