The Effect of Sphingolipids as a New
Therapeutic Option for Acne Treatment
Saskia K. Klee, Mike Farwick, and Peter Lersch
Degussa, Goldschmidt Personal Care, Essen, Germany
The skin is one of the largest organs of the human body. It is a highly specialized tissue that acts as a barrier against the influences of the environment. It plays a crucial role in the protection against dehydration and the control of body tempera- ture (1). The skin’s primary role is to protect our health, but the skin’s barrier is imperfect and it also has the ability to absorb external substances. Moreover, these external substances can access healthy skin via its pilosebaceous glands. Drugs have been detected in the blood stream after topical application, demonstrat- ing transdermal delivery through the skin (2). This is desired for the treatment of many skin diseases, but this characteristic can also be a contributing factor for causing many diverse health risks.
The lipid environment of the stratum corneum is an essential factor for main- taining the skin’s equilibrium. Changes in the barrier lipid composition have been directly linked to skin barrier function impairments, such as pathologically dry and rough skin (3,4). Besides protective tasks, the skin is confronted with a tremendous challenge during puberty, when the increase in circulating levels of testosterone influences the function of pilosebaceous units (PSU) and increases sebogenesis. Increased sebum levels are a major contributory factor in acnegenesis. During puberty, the pituitary gland initiates the sexual maturation process via the release of gonadotropins and the production of hormones called androgens. This process regulates the production of sebum in the sebaceous glands of both adolescent boys and girls (5). This is the time period in which most adolescents develop a more or less severe form of acne. Although superficial and non-life-threatening, acne is a disease that, if left untreated, can have serious physical and psychological consequences (6,7).
Acne is one of the most common skin diseases of human kind, affecting 80% of adolescent boys and girls during puberty (8) that may persist throughout adult- hood, or it may even develop after puberty (commonly known as persistent or late onset acne, respectively) (9). Sebum hypersecretion is the first problem associated with acne-prone skin and is caused by the enzymatic hyperactivity of 5-alpha- reductase—a key enzyme that converts testosterone into dihydrotestosterone (DHT) (5). By binding to its receptor in the skin, DHT stimulates the secretion of sebum (Fig. 1). Men are more severely affected because they produce higher concentrations of androgens that regulate sebum production and enlargement of sebaceous glands (10,11).
The earliest morphological change observed in acne patients is the aberrant follicular epithelial proliferation and differentiation of the PSU that results in clini- cally invisible microcomedones (12 – 15). Due to the hormonal imbalance in
pubescent children, the sebaceous glands overproduce sebum and increase in size (sebaceous hyperplasia). In addition, the exit for sebum—the follicle opening—is obstructed due to an abnormal keratinization of the infundibular epithelium. The horny layer becomes thicker, resulting in the accumulation of corneocytes in the pilosebaceous duct (16,17), and the sebum secretion is hindered. Then the visible comedone, which is a noninflammatory lesion, becomes clinically apparent (Fig. 1).
The skin flora comprises corynebacteria such as Propionibacterium acnes, which are lipophilic bacteria and preferentially occupy the sebum-enriched follicles. High sebum concentration and microscopically small keratinous material lead to a change of the follicular milieu with consecutive proliferation of semi-anaerobic bac- teria, like P. acnes (18). The bacteria secrete a lipase that hydrolyses sebum triglycer- ides to glycerol and free fatty acids, which have proinflammatory and comedogenic properties (19,20). The overproduction of sebum is an ideal condition for the pro- liferation of the bacterial flora. Consequently, the concentration of free sterol levels in the intercorneocytic comedone lipids is further reduced, which leads to an increased corneocyte adhesion and, consequently, to a retention hyperkeratosis (21). In addition, sebocytes themselves are able to synthesize free fatty acids in the absence of bacterial colonization (22), and express the inflammatory cytokine inter- leukin (IL)-1-alpha by an intrinsic mechanism (18). These, together with bacterial cell wall products, set up the inflammatory process. The inflammatory acne lesions, pustules, and papules are then generated.
Depending on the degree of deregulated sebum production, hyperkeratosis, bacterial colonization, and inflammation, acne occurs with increasing severity. The most common form is acne vulgaris, which does not have to be seen by a der- matologist in 70% of cases. More severe forms of acne, like acne conglobata, or forms that induce nodules and pseudocysts need intensive medical care because the formed abscesses coalesce and dissect under the skin to produce highly inflamed sinus tracts (12 – 15). Mild and temporary acne forms occur after hormonal changes in women (23), that is, after giving birth or during menstruation. Newborn children may also show slight signs of acne, which are explained by a temporary androgen overproduction of the adrenal gland (24). Furthermore, acne symptoms may be
induced by cosmetics, medication, and occupational influences (25). Many genetic studies have been performed, and the pathogenesis of acne is well- documented in twins (26); however, further research is needed to investigate the genetic effects.
As the pathogenesis of acne is multifactorial (Fig. 1), the treatment of acne is diverse. Therapies target: (i) sebum production, (ii) hyperkeratinization, (iii) P. acnes, and (iv) the inflammatory response. Hormonal treatment to regulate sebum pro- duction can be applied to young women by the intake of contraceptives. Tretinoin and isotretinoin belong to a family of vitamin A derivatives, and are essential for both the maintenance of epithelial differentiation and the reduction of the hyperpro- liferation of keratinocytes (27,28). Benzoyl peroxide (BPO) acts antimicrobially and shows weak comedolytic activity (29). However, the comedolytic and keratolytic activities of salicylic acid have been shown to be superior to BPO by increased reduction of the total number of acne lesions (30). Multiple antibiotics (tetracycline, erythromycin, and clindamycin) are applied both orally and topically to reduce the number of bacteria. In addition, peeling treatments using, for example, alpha- hydroxy acids (mainly glycolic acid) are used to shed off old cells from the most upper layer of the skin. Recently, Zouboulis (31) has demonstrated that the total lipid level in sebum, especially the proinflammatory lipids, was reduced by a specific lipoxygenase inhibitor, suggesting that the down regulation of acne-related inflam- matory signals is the future therapy. Also, scientists at the Annual Meeting of the Society of Dermopharmacy have proposed a change of paradigm from antibacterial to anti-inflammatory treatment (32). Along these lines, the third-generation retinoid, adapalene, is able to inhibit indirectly the release of cytokines from monocytes and macrophages and thereby suppresses an inflammatory response (33). As a result, other agents that possess anti-inflammatory effects may be a useful adjunct to the anti-acne armory.