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Background: Even with the widespread clinical use of cannabinoid receptor (CBR) stimulating compounds, such as palmitoylethanolamine, the role of CBR agonists on inflammatory skin diseases is not yet fully understood. This study was performed to investigate the effects of CBR agonists on skin inflammation, using acute and chronic inflammation animal models., Methods: The effectiveness of the newly synthesized cannabinoid receptor 1 (CB1R) agonists was determined using in vitro assays. Markers for epidermal permeability barrier function and skin inflammation were measured, and histological assessments were performed for evaluation., Results: Topical application of CB1R-specific agonist significantly accelerated the recovery of epidermal permeability barrier function and showed anti-inflammatory activity in both acute and chronic inflammation models. Histological assessments also confirmed the anti-inflammatory effects, which is consistent with previous reports., Conclusions: All of the results suggest that topical application of CB1R-specific agonist can be beneficial for alleviating the inflammatory symptoms in chronic skin diseases, including atopic dermatitis., (© 2015 The International Society of Dermatology.)

Skin, as the outermost organ in the human body, continuously confronts the external environment and serves as a primary defense system. The protective functions of skin include UV-protection, anti-oxidant and antimicrobial functions. In addition to these protections, skin also acts as a sensory organ and the primary regulator of body temperature. Within these important functions, the epidermal permeability barrier, which controls the transcutaneous movement of water and other electrolytes, is probably the most important. This permeability barrier resides in the stratum corneum, a resilient layer composed of corneocytes and stratum corneum intercellular lipids. Since the first realization of the structural and biochemical diversities involved in the stratum corneum, a tremendous amount of work has been performed to elucidate its roles and functions in the skin, and in humans in general. The perturbation of the epidermal permeability barrier, previously speculated to be just a symptom involved in skin diseases, is currently considered to be a primary pathophysiologic factor for many skin diseases. In addition, much of the evidence provides support for the idea that various protective functions in the skin are closely related or even co-regulated. In this review, the recent achievements of skin researchers focusing on the functions of the epidermal permeability barrier and their importance in skin disease, such as atopic dermatitis and psoriasis, are introduced.

The aim of this study was to assess the effects of chemical and electrical modes of percutaneous penetration enhancement on the intercellular lipid lamellae of the stratum corneum. Hairless mice were treated with either oleic acid/propylene glycol and iontophoresis separately or together. Permeability barrier function was evaluated by measuring transepidermal water loss and correlated with the structure of stratum corneum intercellular lamellae, as evaluated by electron microscopy, using ruthenium tetroxide postfixation. Transepidermal water loss levels did not change following 1 h iontophoresis alone. In contrast, topical applications of 0.3 M oleic acid in propylene glycol for 1 h increased transepidermal water loss significantly. Moreover, the combined use of iontophoresis plus 0.3 M oleic acid for 1 h further increased transepidermal water loss at equivalent time points. Ultrastructural observations demonstrated both marked disorganization of the intercellular lipid lamellae, as well as the presence of distended lacunae within the stratum corneum in oleic acid/propylene glycol plus or minus iontophoresis-treated stratum corneum. This study provides direct evidence that the oleic acid/propylene glycol system can disrupt the stratum corneum lipid lamellar structures, and that coapplications of oleic acid with iontophoresis further enhance the effects of oleic acid. The synergy between chemical and physical enhancement may afford a new approach to promote transdermal drug delivery.

Iontophoresis increases the delivery of drugs across the stratum corneum, but the pathway by which ionized drugs transit the stratum corneum is unknown. In this study we examined the effect of iontophoresis on the skin barrier and the epidermal calcium gradient. Hairless mice were subjected to iontophoresis for 5-120 min and skin specimens were prepared for electron microscopy. Neither positive nor negative iontophoresis affected transepidermal water loss. Lacunar dilatation and partial distention of the intercellular layers of the stratum corneum were observed in rough proportion to applied time in iontophoresis skin as well as control skin. Additionally, using calcium capture cytochemistry, we demonstrated that both positive and negative iontophoresis caused the disappearance of the epidermal calcium gradient with marked decrease in calcium content in the upper epidermis. Positive iontophoresis was associated with increased calcium in the stratum basale and dermis, whereas negative iontophoresis increased calcium in the stratum corneum. Moreover, as previously shown after barrier disruption and sonophoresis, the decrease in calcium content in the upper epidermis was associated with an increase in lamellar body secretion and the build up of lamellar material at the stratum corneum-stratum granulosum interface. In conclusion, iontophoresis on the skin of hairless mice may induce the change of ionized molecules in the epidermis, as the loss of the calcium gradient, which causes the decrease of skin impedence, gives charged drugs the ability to cross the skin more easily. Also, the structural changes, such as lacunar dilatation, whether they result from hydration or occlusion, may help the transport of charged drugs across the stratum corneum.

Abnormal follicular keratinization is important for comedo formation in acne, but the precise mechanism is not known. A recent report about acne vulgaris suggested that an impaired water barrier function may be responsible for comedo formation, since the barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium. Furthermore, the integrity of the water barrier is crucial for the maintenance of the epidermal calcium gradient. Yet stratum corneum intercellular lipid structures, a major factor of the skin barrier function, and calcium distribution in the follicular epithelium of comedones, were not reported. To see SC intercellular lipid and calcium distribution of the follicular epithelium of comedo by electron microscopy, we applied oleic acid on the inner surface of the ear of New Zealand white rabbits to induce comedones, and then we obtained specimens and performed osmium and ruthenium tetroxide postfixation and calcium ion-capture cytochemical procedure. We found incomplete lipid bilayer structures, prominent dilatation of lacunar domains and the loss of follicular epidermal calcium gradient in experimentally induced comedones. From our results, we suggest that the permeability barrier disruption in oleic-acid-applied follicular epithelium can be induced by the changes of SC intercellular membrane structures and lacunar dilatation, and the calcium gradient is lost, so follicular epithelial proliferation and hyperkeratosis can be induced and then comedo formation occurs.