TRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model

Wong, Lai‐San; Otsuka, Atsushi; Yamamoto, Yasuo; Nonomura, Yumi; Nakashima, Chisa; Kitayama, Naomi; Usui, Kenji; Honda, Tetsuya; Kabashima, Kenji

doi:10.1016/j.jdermsci.2017.10.012

Cited by 16 publications

(8 citation statements)

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“…Interestingly, on day 16, MCE ME vehicle ameliorated the DNCB-induced skin similar to the oil-free group ( P >0.05), and both of them were greater than the commercial ointment ( P <0.05), which indicated that the vehicle containing MCE could decrease AD symptoms and the lower concentration of surfactant and co-surfactant in MCE ME did not irritate the AD-like skin. The commercial ointment irritates skin, resulting in erythema, dryness, and itching in AD patients 22. Moreover, we observed that it is difficult for the commercial ointment with sticky ointment to spread out on the impaired skin during the treatment.…”

Section: Resultsmentioning

confidence: 84%

“…The transient irritations mainly associated with the drug characteristic of TCIs 19. TCIs can activate the transient receptor potential A1 (TRPA1) channel followed by SP release, which induces the initial side effects of burning and itching during the therapy with FK506,20–22 and itch-triggered scratching immediately leads to symptom exacerbation, and pruritus–scratch–pruritus easily turns into a vicious circle. These irritations of FK506 in AD patients often lead to treatment discontinuation.…”

Section: Introductionmentioning

confidence: 99%

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<p>Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects</p>

Wang¹,

Cao²,

Yu³

et al. 2019

IJN

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Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1–chloro–2, 4–dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537)

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Section: Resultsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

<p>Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects</p>

Wang¹,

Cao²,

Yu³

et al. 2019

IJN

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“…FK506-induced pancreatitis-related pain was attenuated by an antagonist of TRPV1, but not by voltage-gated Ca 2+ channels in mice [44]. FK506 enhanced TRPA1 expression in a murine model of oxazolone-induced chronic hypersensitivity and FK506-induced scratching behaviors were reduced by a TRPA1 antagonist [57]. In this study, we found that local injection of FK506 induced acute licking or biting behaviors through TRPA1 activation (Fig.…”

Section: Discussionmentioning

confidence: 56%

FK506 (tacrolimus) causes pain sensation through the activation of transient receptor potential ankyrin 1 (TRPA1) channels

et al. 2018

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FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca 2+ -imaging experiments, increases in intracellular Ca 2+ concentrations ([Ca 2+ ] i ) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca 2+ ] i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.

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“…TRPA1 involvement can also occur downstream, particularly in models which have a defined receptor target associated with itch, e.g., using SLIGRL to activate MrgprC11 [41], chloroquine to activate Mrgpra3/X1 [42], serotonin to activate HTR7 [43], TSLP to activate the TSLP receptor [44], and IL31 to activate the IL31 receptor [45]. These diverse mediators converge on common pathways as modulating G protein-coupled receptors, and TRPA1 has been shown to be essential in these pathways [46,47,48,49].…”

Section: Symptomatic Therapy—antipruritic Potentialmentioning

confidence: 99%

“…Atopic dermatitis is a burdensome allergic disease with therapy-resistant chronic itch as a hallmark. In an oxazolone-based animal model of chronic dermatitis, TRPA1 inhibition could reduce scratching [47]. Scratching induced by IL-13 or IL-31 in atopic dermatitis models was reduced in TRPA1-deficient mice or by TRPA1 inhibition [45,50].…”

Section: Symptomatic Therapy—antipruritic Potentialmentioning

confidence: 99%

Non-Analgesic Symptomatic or Disease—Modifying Potential of TRPA1

Heber

Fischer

2019

Medical Sciences

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TRPA1, a versatile ion channel of the Transient Receptor Potential (TRP) channel family, detects a large variety of chemicals and can contribute to signal processing of other stimuli, e.g., due to its sensitivity to cytosolic calcium elevation or phosphoinositolphosphate modulation. At first, TRPA1 was found on sensory neurons, where it can act as a sensor for potential or actual tissue damage that ultimately may elicit pain or itch as warning symptoms. This review provides an update regarding the analgesic and antipruritic potential of TRPA1 modulation and the respective clinical trials. Furthermore, TRPA1 has been found in an increasing amount of other cell types. Therefore, the main focus of the review is to discuss the non-analgesic and particularly the disease-modifying potential of TRPA1. This includes diseases of the respiratory system, cancer, ischemia, allergy, diabetes, and the gastrointestinal system. The involvement of TRPA1 in the respective pathophysiological cascades is so far mainly based on pre-clinical data.

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TRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model

Abstract: Letter to the EditorTRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model Keywords Tacrolimus TRPA1 channel Atopic dermatitis Contact hypersensitivity

Cited by 16 publications

References 10 publications

<p>Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects</p>

<p>Integrating tacrolimus into eutectic oil-based microemulsion for atopic dermatitis: simultaneously enhancing percutaneous delivery and treatment efficacy with relieving side effects</p>

FK506 (tacrolimus) causes pain sensation through the activation of transient receptor potential ankyrin 1 (TRPA1) channels

Non-Analgesic Symptomatic or Disease—Modifying Potential of TRPA1

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