The Effect of Sphingolipids

15 May

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

INTRODUCTION

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.

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