Scientific Background of Hexadeltine

Scientific Background of Hexadeltine

Hexadeltine is our trade name for the Hexapeptide Tyr- D-Ala-Gly-Phe-Leu-Asp. It is an enkephalin analogue and acts as delta-opioid agonist on receptors expressed on keratinocytes. The INCI name is Hexapeptide-18. Delta-opioid receptors couple through G proteins to adenylate cyclase and cAMP phosphodiesterase. Delta-opioid agonists inhibit thus intracellular cAMP concentrations. This reduction of cAMP levels determines the dermatological profile of Hexadeltine which consists of activating microcirculation, inhibiting melanogenesis, inhibiting over-expression of IL-1 alpha by keratinocytes and their proliferation. The latter effect antagonizes potential exfoliation of skin promoted by Dermatopoietin®.

Effect on the release of IL-1 alpha by keratinocytes 
The effect of Hexadeltine on the production and release of IL-1 alpha was studied in cultured human keratinocytes. They were treated for one hour with Dermatopoietin®, Hexadeltine or a mixture of both (Dermatopoietin®-Plus). After this incubation period the keratinocytes were washed, resuspended and the release of IL-1 alpha into the medium measured after 3, 24 and 48 hours.  The results showed that Hexadeltine itself enhances the release of IL-1 alpha but to a much lower extent than Dermatopoietin®. But interestingly, Hexadeltine inhibits the Dermatopoietin®-induced release of IL-1 alpha, especially at the longer time points. For detailed experimental results see scheme A and scheme B.

From these results it is evident that Hexadeltine controls the production of IL-1 alpha in response to exogenous Dermatopoietin®: it curtails the autocrine stimulation of IL-1 alpha release and prevents IL-1 alpha concentration from overshooting. The mixture of Dermatopoietin® and Hexadeltine (Dermatopoietin®-Plus) shows thus optimal properties to generate a controlled, less than 24-hour lasting stimulus to rebuild skin structure upon daily application of a cosmetic preparation.

Hexadeltine is an activator of skin microcirculation 
A randomized, double-blind, placebo-controlled study using  Laser Doppler flowmetry showed that Hexadeltine increases microcirculation in skin (see Figure).

Hexadeline does not penetrate skin 
The absorption and penetration of Hexadeltine was measured by exposing artificial human skin patches during 24 hours to high concentrations of fluorescence-labeled Hexadeltine (about 880 times higher than the in-use concentration). Fluorescence microscopy indicated that Hexadeltine was absorbed by the stratum corneum only without penetrating deeper layers. The detection limit of this method was estimated to be 20 pg/cm2.

Left figure: fluorescence microscopy. Green fluorescence indicates the presence of labeled Hexadeltine.

Right figure: light microscopic picture of the same field showing the artificial epidermis (EpiSkin) on a supporting polycarbonate membrane (arrow). Magnification: 100 x. Small circle: 10 m, large circle: 25 m

Mechanism of action 
Hexadeltine does, similar to Dermatopoietin®, not penetrate skin. It exerts its 'soothing' effects by activating a signal cascade by interacting with delta receptors on the first layer of living keratinocytes in the epidermis.