MECHANISM OF ACTION OF OCTADECENEDIOIC ACID | Kickoff

MECHANISM OF ACTION OF OCTADECENEDIOIC ACID

15 May

The clinical  study using  DCA clearly  demonstrated an efficacy toward acne, albeit that   the   delivery  of  the   active   ingredient  could   still  be  improved.  However, the reduction in P. acnes in the second study was minimal, and  this is typically con- sidered to  be  essential for  any  active  ingredient  to  exert  an  anti-acne  activity. Although an  antimicrobial activity   of  DCA  could   not  be  denied (Table  1),  this alone  was  not  enough to  explain its  activity  in  patients suffering from  mild-to- moderate acne. In finding an explanation for this contradiction, the data  in Table 3 turned out  to  be  of  crucial   importance.  Whereas the  vehicle   alone   resulted in scaling in 60% of patients, the addition of DCA reduced this percentage considerably to 13% and  20%, suggesting an  anti-inflammatory side  effect  of DCA.  A separate study did   indeed  suggest a  slight   anti-inflammatory  activity,   albeit  statistically insignificant (data  not shown). As inflammation in the human skin is regulated via the  PPAR,  we  investigated whether DCA,  an  unsaturated fatty  acid,  did  indeed bind  to this receptor. After all, fatty acids are the typical  ligands for these  receptors.

A reporter gene  assay  using  HeLa  cells transfected with  chimeric receptor genes   fused   to  a  PPAR  ligand-binding domain  and   a  reporter gene  with   the luciferase/luciferine  system was  performed. Separate cell  lines  were  developed for   PPARa,  d,  and   g.  A   total   of  2.5     104    cells   were   plated  into   96-well microtiter  plates   with   phenol  red-free  Dulbecco’s   Modified  Eagles   Medium (DMEM)  culture media containing 6% dextran-coated, charcoal-treated fetal  calf serum (DCC  FCS).  Cells  were   incubated  with   pharmaceutical  PPAR  agonists (10211 2 1025  M), DCA  (1027 –1025  M), or  pioglitazone [1028 –1025  M; a positive control  for  PPARg  binding (22)] for  16 hours, and  at  the  end  of the  incubation, the medium was removed and replaced with culture medium containing luciferine and  a luminescent signal  measured after  five minutes using  a Microbeta lumin- ometer (Wallac, Turku, Finland). All experiments were performed in quadruplicate.

These  experiments, the  results of which  are illustrated in Figure  9, showed that DCA is a pan-PPAR agonist with  a greater specificity  for PPARg. As a specific PPARg  agonist, pioglitazone naturally only  binds  to  PPARg.  Other  controls for PPARa and  PPARd were  included but not shown here (13).

FIGURE 9    Induction of luciferase expression by octadecenedioic acid (A) and  pioglitazone (B) in three  separate HeLa  cell lines  expressing peroxisome proliferator-activated receptor a, d, and  g separately. Abbreviation:  PPAR,  peroxisome proliferator-activated receptor.

RATIONALE FOR OCTADECENEDIOIC  ACID AS A NOVEL TOPICAL ACNE TREATMENT

Acne is a common disease affecting,  according to surveys, nearly  one out of three teenagers, although the disease is not  limited to preadolescents only.  It markedly influences the quality of life and  constitutes a socio-economic problem. Worldwide costs for systemic and  topical  acne treatment were calculated to represent 12.6% of the annual overall  costs for the treatment of skin  diseases (23). Its pathogenesis is multifactorial, with  abnormal follicular  differentiation and  increased cornification, enhanced sebaceous gland activity  and  hyperseborrhea, bacterial hypercoloniza- tion  as well  as inflammation, and  immunological host  reactions being  the  major contributors  (23).  It  is  characterized  by  a  variety  of  expressions  and   degrees depending on the  distribution, type  of lesions,  tendency to and  manifestation  of scarring, start  of  disease in  puberty, or  persistence after  time  of  physiological

regression, each form requiring a different active ingredient or drug or combination thereof  (24).

There  are  basically  four  modes of action  for  treating acne  in  line  with  the pathogenesis described earlier: most anti-acne agents have an antimicrobial activity to counteract the hypercolonization (in particular, e.g., BPO), some  agents interact with the hyperkeratinization aspect of acne to fight the abnormal follicular differen- tiation  and increased cornification (in particular, the retinoids such as tretinoin, iso- tretinoin, and  adapalene), a few have  only  a moderate anti-inflammatory activity (e.g., adapalene, AZA,  and  BPO), whereas none  have  a strong sebo-suppressive effect to fight the hyperseborrhea (24). Because  of the complexity of the disease, it is very  difficult  to differentiate between cause  and  effect, and  as a consequence, relapses often  occur  because the  fundamental underlying cause  may  not  have been  dealt  with.  As a consequence, combination therapies are popular, involving both  the  topical  and  the  oral  route  of administration. Mammone et  al.  (25), for instance, proposed a combination of chemicals with antimicrobial, anti-inflammatory, and antiandrogen properties and a desquamation enhancer, resulting in a statistically significant higher reduction in noninflamed lesions relative to a 5% BPO gel, whereas there  was  no  statistically significant additional  benefit  toward inflamed lesions. The downside of combination therapy, however, is that  this increases the chance  of side effects, as most  of these  products have  some.  AZA, for instance, causes  a very strong burning and BPO results in strong scaling and erythema (24), which  was con- firmed  in our studies (Table 3).

Here,  we  report the  use  of DCA  as  a novel  topical  treatment of acne  that involves all four  modes of action  within a single  molecule. Similar  to most  other anti-acne agents, DCA  has  an  antimicrobial activity  as  indicated in  Table  1. All three  other  modes of action  may  be produced via its binding to PPAR, as shown in Figure  9, which  illustrates its capability to act as a pan-PPAR agonist. Binding to PPARg  is most  pronounced, followed by that  to PPARa and  PPARd. As shown by Downie et al. (5), activators of PPARa and  PPARg inhibit  the rate of sebaceous lipogenesis and reduce the synthesis of the sebum-specific lipids  squalane and tria- cylglycerol in human sebaceous glands. DCA, as a PPARg  and  PPARa agonist, is therefore likely  to do the same,  provided it is delivered well enough. The import- ance of PPAR in the regulation of lipid  synthesis and  metabolism in human sebo- cytes  is recognized, albeit  far  from  clear  yet.  Makrantonaki and  Zouboulis (26), for instance, described the stimulatory interactions between androgens and  PPAR ligands, similar to the natural PPARd/g ligand linoleic  acid,  on neutral and  polar lipid  synthesis. Although linoleic  acid  is stimulating lipid  synthesis in  vitro  in this communication (26), topical  administration of 2.5% linoleic acid in a Carbopol gel  formulation for  one  month resulted in  a  significant reduction  (25%) in  the overall   size  of  follicular   casts  and   microcomedones, whereas  no  change   was found at placebo-treated sites (27). Further research will be necessary to elucidate the interrelationships between all factors  involved.

DCA,  however, is one  of the  very  few  molecules that  has  the  potential to interact at all levels  with  acne: enhanced differentiation to prevent the increased cornification of the  sebaceous duct  (via PPARd), reduction in sebum production to   counteract  hyperseborrhea  (via   PPARg),   and   reduction  in   inflammation (PPARa). These PPAR-related effects combined with  its demonstrated antimicro- bial properties to overcome the hypercolonization with  microbes such  as P. acnes and  S. aureus,  make  DCA  a  viable  nonantibiotic alternative for  the  treatment of acne.

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