Osthole inhibits histamine-dependent itch via modulating TRPV1 activity

Yang, Niuniu; Shi, Hao; Yu, Guang; Wang, Changming; Zhu, Changliang; Yang, Yan; Yuan, Xiaolin; Tang, Min; Wang, Zhongli; Gegen, Tana; He, Qiang; Tang, Kaibin; Lan, Lei; Wu, Guanyi; Tang, Zongxiang

doi:10.1038/srep25657

Cited by 32 publications

(42 citation statements)

References 42 publications

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“…As the most common pruritogen, histamine can produce itch associated with wheal and flare in human skin (Sun and Dong, 2016). Yang et al (2016) recently reported that osthole inhibited histamine-induced acute itching. To further confirm the effect of osthole on acute histamine-dependent itch, we adopted a pretreatment by intradermal injection with osthole into the mouse neck before injection with histamine into the same site.…”

Section: Inhibition Of Trpv3 Channel By Natural Coumarinmentioning

confidence: 99%

“…Many studies on C. monnieri have focused on antipruritic action of the extracts as well as the ingredients purified from the plant extracts in rodent animal models. Yet, the critical ingredients from the C. monnieri plant used for antipruritus and their mechanisms of action still remain elusive, although Yang et al (2016) recently reported that osthole inhibits capsaicin-induced calcium influx and inward TRPV1 current in cultured small dorsal root ganglion neurons in which other TRPs channels are also expressed (Kittaka and Tominaga, 2017).…”

Section: Osthole Attenuates Pruritus Through Selective Inhibition Of mentioning

confidence: 99%

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Antipruritic Effect of Natural Coumarin Osthole through Selective Inhibition of Thermosensitive TRPV3 Channel in the Skin

Sun

et al. 2018

Mol Pharmacol

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Coumarin osthole is a dominant bioactive ingredient of the natural plant commonly used for traditional Chinese herbal medicines for therapies and treatments including antipruritus and antidermatitis. However, the molecular mechanism underlying the action of osthole remains unclear. In this study, we report that osthole exerts an antipruritic effect through selective inhibition of Ca-permeable and thermosensitive transient receptor potential vanilloid 3 (TRPV3) cation channels that are primarily expressed in the keratinocytes of the skin. Coumarin osthole was identified as an inhibitor of TRPV3 channels transiently expressed in HEK293 cells in a calcium fluorescent assay. Inhibition of the TRPV3 current by osthole and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV3-expressing HEK293 cells and mouse primary cultured keratinocytes. Behavioral evaluation demonstrated that inhibition of TRPV3 by osthole or silencing by knockout of the 3 gene significantly reduced the scratching induced by either acetone-ether-water or histamine in localized rostral neck skin in mice. Taken together, our findings provide a molecular basis for use of natural coumarin osthole from the plant in antipruritic or skin care therapy, thus establishing a significant role of the TRPV3 channel in chronic itch signaling or acute histamine-dependent itch sensation.

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Section: Inhibition Of Trpv3 Channel By Natural Coumarinmentioning

confidence: 99%

Section: Osthole Attenuates Pruritus Through Selective Inhibition Of mentioning

confidence: 99%

Antipruritic Effect of Natural Coumarin Osthole through Selective Inhibition of Thermosensitive TRPV3 Channel in the Skin

Sun

et al. 2018

Mol Pharmacol

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“…Notably, osthole significantly reduced intracellular Ca 2+ mobilization induced by the MRGPRX2 ligands. Several previous studies have suggested that osthole can block Ca 2+ channels to affect cellular responses (62)(63)(64). For example, a recent study by Su et al, (62) showed that osthole can inhibit neuropathic pain behaviors through inhibition of T-and L-type Ca 2+ currents in nociceptive DRG neurons.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a recent study by Su et al, (62) showed that osthole can inhibit neuropathic pain behaviors through inhibition of T-and L-type Ca 2+ currents in nociceptive DRG neurons. Additionally, osthole blocks TRPV channels to prevent pruritis and dermatitis in animal models (63,64). While it is still unclear whether MRGPRX2 responses in mast cells function via the T-and L-type or TRPV channels, it is plausible that osthole inhibits mast cell activation by blocking these channels resulting in reduced downstream responses such as degranulation and cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

et al. 2020

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Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca 2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2-(mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.

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“…In recent years, we have paid great attention to the mechanisms of traditional Chinese medicine in the relief of itch. We have found that osthole, an active coumarin isolated from herb Cnidium monnieri (L.) Cusson, which has been long used in China as an antipruritic herbal medicine, inhibits histamine-dependent itch by modulating TRPV1 activity [11]. However, osthole has no effect on the histamine-independent pruritus, limiting its clinical application.…”

Section: Short Communicationmentioning

confidence: 99%