Hyperforin/HP- β -Cyclodextrin Enhances Mechanosensitive Ca 2+ Signaling in HaCaT Keratinocytes and in Atopic Skin Ex Vivo Which Accelerates Wound Healing

Cutaneous wound healing is accelerated by mechanical stretching, and treatment with hyperforin, a major component of a traditional herbal medicine and a known TRPC6 activator, further enhances the acceleration. We recently revealed that this was due to the enhancement of ATP-Ca signaling in keratinocytes by hyperforin treatment. However, the low aqueous solubility and easy photodegradation impede the topical application of hyperforin for therapeutic purposes. We designed a compound hydroxypropyl- -cyclodextrin- (HP- -CD-) tetracapped hyperforin, which had increased aqueous solubility and improved photoprotection. We assessed the physiological effects of hyperforin/HP- -CD on wound healing in HaCaT keratinocytes using live imaging to observe the ATP release and the intracellular Ca increase. In response to stretching (20%), ATP was released only from the foremost cells at the wound edge; it then diffused to the cells behind the wound edge and activated the P2Y receptors, which caused propagating Ca waves via TRPC6. This process might facilitate wound closure, because the Ca response and wound healing were inhibited in parallel by various inhibitors of ATP-Ca signaling. We also applied hyperforin/HP- -CD on an ex vivo skin model of atopic dermatitis and found that hyperforin/HP- -CD treatment for 24 h improved the stretch-induced Ca responses and oscillations which failed in atopic skin.