Stratum corneum ceramides are major determinants of skin barrier function. Although their physiological and pathological role has been widely investigated, to date no structure-activity relationships have been established. In this study, a series of short-chain ceramide analogues with polar head structure identical to ceramide NS, a sphingosine length of 12 carbons and an acyl chain length of 2-12 carbons was synthesized. Their effect on skin permeability was evaluated using porcine skin and two model drugs, theophylline and indomethacin, and compared to that of a physiological ceramide NS. The results showed that the ceramide chain length was crucial for their barrier properties. Ceramides with a 4- to 8-carbon acyl chain were able to increase skin permeability for both drugs up to 10.8 times with maximum effect at a 6-carbon acyl chain. No increase in permeability was found for ceramide analogues with 2- and 12-carbon acyl chains and ceramide NS. The same relationships were obtained for skin concentrations of the model drugs. The relationship between ceramide acyl chain length and its ability to perturb skin barrier showed striking similarity to the behavior of short-chain ceramides in sphingomyelin/phospholipid membranes and confirmed that short-chain ceramides do not act as natural ceramides and their use as experimental tools should be cautious.

• MeSH
• ceramidy chemická syntéza   farmakologie   MeSH
• indomethacin metabolismus   MeSH
• kožní absorpce účinky léků   MeSH
• kůže chemie   účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• permeabilita MeSH
• prasata MeSH
• theofylin metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ceramidy MeSH
• indomethacin MeSH
• theofylin MeSH

Omega-O-acylceramides (acylCer), a subclass of sphingolipids with an ultralong N-acyl chain (from 20 to 38 carbons, most usually 30 and 32 carbons), are crucial components of the skin permeability barrier. AcylCer are involved in the formation of the long periodicity lamellar phase (LPP, 12-13 nm), which is essential for preventing water loss from the body. Lower levels of acylCer and LPP accompany skin diseases, such as atopic dermatitis, lamellar ichthyosis, and psoriasis. We studied how the concentration and structure of acylCer influence the organization and permeability barrier properties of model lipid membranes. For simple model membranes composed of the sphingosine-containing acylCer (EOS), N-lignoceroyl sphingosine, lignoceric acid, cholesterol (Chol), and cholesteryl sulfate (CholS), the LPP formed at 10% Cer EOS (of the total Cer) and the short periodicity phase disappeared at 30% Cer EOS. Surprisingly, membranes with the LPP had higher permeabilities than the control membrane without acylCer. In the complex models consisting of acylCer (EOS, phytosphingosine EOP, dihydrosphingosine EOdS, or their mixture; at 10% of the total Cer), a six-component Cer mixture, a free fatty acid mixture, cholesterol (Chol), and cholesteryl sulfate (CholS), acylCer decreased the membrane permeability to model permeants (with the strongest effects for acylCer EOP and EOdS) when compared with the permeability of the control membrane without acylCer. However, in the complex model, only a mixture of acylCer EOS, EOdS, and EOP and not the individual acylCer formed both the LPP and orthorhombic chain packing at the 10% level. Thus, the relationships between acylCer, LPP formation, and permeability barrier function are not trivial. Lipid heterogeneity is essential-only the most complex model with nine Cer subclasses mimicked both the organization and permeability of stratum corneum lipid membranes.

• MeSH
• ceramidy chemie   MeSH
• epidermis chemie   účinky léků   MeSH
• kožní absorpce * MeSH
• lidé MeSH
• membrány umělé * MeSH
• permeabilita MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ceramidy MeSH
• membrány umělé * MeSH