Modulators of the endocannabinoid system influence skin barrier repair, epidermal proliferation, differentiation and inflammation in a mouse model

Endocannabinoids (ECs) are important regulators of cell signalling. Cannabinoid receptors are involved in keratinocyte proliferation/differentiation. Elevation of the endogenous cannabinoid tone leads to strong anti-inflammatory effects. Here, we explored the influence of endocannabinoid system (ECS) modulators on skin permeability barrier repair, epidermal proliferation, differentiation and inflammation in hairless mice. We used WOBE440, a selective fatty acid amide hydrolase (FAAH) inhibitor, WOL067-531, an inhibitor of endocannabinoid reuptake with no relevant FAAH activity, which both signal via cannabinoid receptor-1 and cannabinoid receptor-2 (CB-1R and CB-2R) and compared them to WOBE15 which signals via CB-2R. Barrier disruption and skin irritation were induced by tape stripping or by sodium dodecyl sulphate (SDS) patch testing. Immediately after barrier disruption, 30 mu L of 0.5% WOBE440, WOL067-531 and WOBE15 solutions or the vehicle was applied topically. Barrier repair was monitored by transepidermal water loss at 1.5, 3, 5 and 7 hours. We found that barrier repair was significantly delayed by WOL067-531. A tendency for a delay was noticed for WOBE440, whereas for WOBE15, no effect was observed. Immunohistology showed that the tape-stripping-induced increase in epidermal proliferation and filaggrin expression was significantly reduced by topical applications of WOL067-531 and WOBE440, but not by WOBE15. Also, the SDS-induced inflammation, as determined by the number of inflammatory cells, was reduced by WOL067-531 and WOBE440. In summary, we showed that WOL067-531 exhibits a significant effect on skin barrier repair, epidermal proliferation/differentiation and inflammation.