Treatment with Synthetic Pseudoceramide Improves Atopic Skin, Switching the Ceramide Profile to a Healthy Skin Phenotype

Abstract

Little is known about the pathophysiological linkages between altered ceramide profiles in the stratum corneum (SC) of patients with atopic dermatitis and their impaired skin barrier and water-holding functions. We studied those characteristics following topical treatment with a designed synthetic pseudoceramide (pCer) and analyzed that pathophysiological linkage by microanalyzing ceramides using normal phase liquid chromatographyeelectrospray ionization mass spectrometry. Four weeks of treatment with pCer significantly reduced skin symptoms, accompanied by significant decreases in transepidermal water loss and increases in water content. In the SC ceramide profiles, ceramides containing nonhydroxy fatty acids and 6hydroxysphingosines (Cer[NH]) and ceramides containing nonhydroxy fatty acids and phytosphingosines (Cer[NP]) increased, whereas ceramides containing nonhydroxy fatty acids and sphingosines (Cer[NS]) and ceramides containing a-hydroxy fatty acids and sphingosines (Cer[AS]) decreased, with larger alkyl chain lengths in Cer[NS], distinctly representing a switch from an atopic dermatitis to a healthy skin phenotype. The level of pCer that penetrated into the SC was significantly correlated with the SC water content but not with transepidermal water loss. The level and the average carbon chain length of Cer[NS] were closely correlated with the pCer level in the SC. These findings indicate that the penetrated pCer contributes to shift the ceramide profile from an atopic dermatitis to a healthy skin phenotype. Taken together, the observed clinical efficacy of treatment with pCer provides a deep insight into the pathogenesis of atopic dermatitis as a ceramide-deficient disease.

Cutting Edge of the Pathogenesis of Atopic Dermatitis: Sphingomyelin Deacylase, the Enzyme Involved in Its Ceramide Deficiency, Plays a Pivotal Role

“…Thus, it seems reasonable to assume that the disrupted keratinization process that occurs subsequently due to cutaneous inflammation is mainly attributable to the ceramide profile changes, thereby exacerbating the pathological changes. This fact was also corroborated by our recent study which demonstrated that repetitive topical applications of pCer to AD skin significantly improved inflammation and atopic dry skin as well as the SC barrier/water reservoir function, accompanied by switching the ceramide profile to a healthy skin phenotype (Figure 3) [12]. Interestingly, these clinical and functional improvements in the SC can be achieved without any restoration of the decreased levels of total endogenous ceramides to a healthy state but with applied and compensated pCer accumulating at a similar level to existing endogenous ceramides in the SC.…”

“…The AD dry skin is also distinctly accompanied by both the cutaneous barrier disruption and an impaired water-holding capacity in the stratum corneum (SC) [3][4][5][6][7][8][9][10], features that contrast with xerosis [11] and contact dermatitis where there is no barrier abnormality in nonlesional skin, providing clinical insights into the pathogenesis of AD. The close relationship between the AD skin symptoms and SC functions has been well established in several clinical studies with AD patients including our group [3][4][5][6][7][8][9][10]12]. Thus, in one of our clinical studies with AD patients [4], comparison of SC functions with dry skin scores on the nonlesional AD skin demonstrated that while the capacitance values were highly correlated with dryness scores (r = −0.752, p < 0.0001, n = 106) and with scaling scores (r = −0.697, p < 0.0001, n = 106), the transepidermal water loss (TEWL) was also paralleled by dryness (r = 0.788, p < 0.0001, n = 106) with a higher correlation coefficient compared with capacitance values and scaling scores (r = 0.697, p < 0.0001, n = 106).…”

“…This suggests that total ceramide levels, including penetrated pCer in the SC, are more essential to restoring and maintaining the barrier and water reservoir functions than are the differential ceramide profiles and play an essential role in improving clinical skin symptoms. Thus, almost all topical application studies [5][6][7][8][9][10]12,32] of pCer on nonlesional AD skin demonstrated that compensating ceramide levels in AD nonlesional SC is significantly effective in improving atopic dry skin, accompanied by the amelioration of disrupted barrier and water holding functions as well as by switching the endogenous ceramide profile to a healthy skin phenotype [12]. These findings strongly suggest that the ceramide deficiency rather than altered ceramide profiles in the SC of AD skin plays an essential role in the pathogenesis of AD.…”

“…Furthermore, RTLC analysis of reaction products generated by fraction peak II demonstrated that the enzyme possesses activity that can release radiolabeled SPC ( Figure 12B). Taken together, it is likely that the enzymatic characteristics of SM deacylase account for the deficiencies in some species of ceramides seen in the SC of AD skin [12], which provides an etiological basis for the dry and barrier-disrupted skin of AD patients. Taken together, it is likely that the enzymatic characteristics of SM deacylase account for the deficiencies in some species of ceramides seen in the SC of AD skin [12], which provides an etiological basis for the dry and barrier-disrupted skin of AD patients.…”

Sphingomyelin Deacylase, the Enzyme Involved in the Pathogenesis of Atopic Dermatitis, Is Identical to the β-Subunit of Acid Ceramidase

“…Further, the lipid lamellar organization in the SC of AD skin with perturbed barrier and water reservoir functions is distinctly altered as a result of changes in ceramide profiles including the ceramide composition and their alkyl chain lengths [17]. The essential role of the ceramide deficiency in the pathogenesis of AD is also corroborated by our recent study demonstrating that repetitive topical applications of a synthetic pseudo-ceramide (pCer) to AD skin significantly improved inflammation and atopic dry skin as well as the SC barrier/water reservoir function by switching the ceramide profile to a healthy skin phenotype [18]. Nevertheless, these clinical and functional improvements in the SC can be achieved without any recovery of the decreased levels of total endogenous ceramides but with applied and compensated pCer remaining at a similar level to existing endogenous ceramides.…”