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

Kita, Tomo; Uchida, Kunitoshi; Kato, Koichi; Suzuki, Yoshiro; Tominaga, Makoto; Yamazaki, Jun

doi:10.1007/s12576-018-0647-z

Cited by 13 publications

(9 citation statements)

References 60 publications

(72 reference statements)

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“…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%

<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: 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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“…FKBPs regulate intracellular ryanodine and IP 3 receptor Ca 2+ release channels (Bultynck et al, 2000;MacMillan, 2013). Recently, it has been reported that FK506 induces Ca 2+ influx via TRPA1 channels (Bultynck et al, 2000;Kita et al, 2019). B16F10, a mouse melanoma cell line, has been widely used as a transplantable murine melanoma model (Burghoff et al, 2014;Chen et al, 2019;Langer et al, 2006;Overwijk & Restifo, 2001).…”

Section: Introductionmentioning

confidence: 99%

Elevation of TRPV1 expression on T-cells during experimental immunosuppression

et al. 2022

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An intracellular rise in calcium (Ca 2+ ) is an essential requisite underlying T cell activation and its associated pro-inflammatory cytokine production. Transient receptor potential vanilloid channel (TRPV1) is a thermo-sensitive, polymodal gated and permeable to cations such as Ca 2+ . It has been reported that TRPV1 expression increases during T cell activation. However, the possible involvement of TRPV1 during immunosuppression of T cells has not been studied yet. Here, we investigated the possible role of TRPV1 in FK506 or B16F10-culture supernatant (B16F10-CS) driven experimental immunosuppression in T cells. Intriguingly, it was found that TRPV1 expression is further elevated during immunosuppression compared to ConA or TCR activated T cells. Similarly, in B16F10 tumor-bearing mice, the TRPV1 expression was upregulated in T cells as compared to control mice, in vivo. Moreover, we observed an immediate rise in intracellular Ca 2+ levels in FK506 and B16F10-CS treated T cells as compared to ConA or TCR treated T cells. Likewise, in B16F10 tumor-bearing mice, the basal intracellular calcium level was upregulated in T cells as compared to control mice, in vivo. To further investigate the possible mechanism of such rise in intracellular Ca 2+ levels, TRPV1 specific functional inhibitor, 5 -iodoresiniferatoxin (5 -IRTX) was used in calcium influx studies. It was observed that the total intracellular Ca 2+ levels decreased significantly in presence of 5 -IRTX for either the FK506 or B16F10-CS as well as with ConA or TCR stimulated T cells, indicating the functional role of TRPV1 channels in FK506 or B16F10-CS mediated increase in intracellular Ca 2+ levels. The current findings highlight an essential role of the TRPV1 channel in upregulating intracellular calcium levels during both immune-activation and immunosuppression. This study might also have broad implications in the context of other immune-suppressive diseases as well.

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“…Local application of FK506 might evoke burning sensations, and some patients have felt pain after using FK506 topically. The underlying mechanism might be explained by FK506 mediating TRPA1 activation 83 . To lower the side effects of FK506, a microemulsion system integrating FK506 into a menthol/camphor eutectic might be helpful, owing to their cooling nature in topical analgesics 84 …”

Section: Management Of Pain In Admentioning

confidence: 99%

Characteristics, mechanism, and management of pain in atopic dermatitis: A literature review

Dong

2021

Clinical & Translational All

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Background Atopic dermatitis (AD) is a chronic, pruritic, immune‐mediated inflammatory disease. Developments in basic science and clinical research have increased our understanding of AD. Although pain as a symptom of AD is underemphasized in previous studies, multiple researchers address pain as a frequent burden of AD. However, the exact role of pain in AD is not fully understood. Aims Our review aimed to summarize the current evidence focusing on characteristics, mechanism, and management of pain in AD. Materials & Methods We conducted a thorough literature review in the PubMed database to figure out different aspects discussing pain in AD, including pain symptoms, burden, the relationship between pain and itch, mechanism, and pain management in AD. Results and Conclusion AD patients affected by skin pain vary from 42.7%‐92.2% with remarkable intensity and heavy burden. Skin pain and itch interacted both in symptoms and mechanisms. Atopic skin with the impaired barrier, neurogenic inflammation mediators, peripheral and central sensitization of pain may possibly explain pain mechanism in AD. Future research is needed to clarify the commonality and disparity of pain and itch in AD in order to seek efficacious medications and treatment.

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

Cited by 13 publications

References 60 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>

Elevation of TRPV1 expression on T-cells during experimental immunosuppression

Characteristics, mechanism, and management of pain in atopic dermatitis: A literature review

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