A new therapeutic approach to treat psoriasis by inhibition of fatty acid oxidation by Etomoxir.
BACKGROUND
The dogma in psoriasis is that due to pathogen-induced inflammatory responses, an autoreactive immune response is induced that leads to tissue destruction. However, this model might be too simplistic. Literature data suggest that the expression of enzymes crucial for fatty acid oxidation is upregulated in the skin of patients with psoriasis compared with healthy individuals.


OBJECTIVE
To examine the influence of fatty acid oxidation on psoriasis with regard to expression and activity of the key enzyme in fatty acid oxidation, carnitine palmitoyltransferase-1 (CPT-1) and the effect of the CPT-1 inhibitor, Etomoxir.


METHODS
Experiments were performed with homogenates of lesional and healthy skin, fibroblast cultures and a model of human psoriatic skin transplanted on immune-deficient BNX mice.


RESULTS
CPT-1 was highly active in lesional skin. Etomoxir was able to block CPT-1 activity in skin, implying that this antagonist may have the potential to suppress psoriasis when administered topically. In the mouse model, Etomoxir had an antipsoriatic effect that was at least as good as that of betamethasone, as evidenced by reduction of epidermal thickness, keratinocyte proliferation and differentiation.


CONCLUSIONS
We conclude that fatty acid metabolism and in particular CPT-1 may be an excellent target for treatment of psoriasis.
Caspary
F
F
Medigene AG, Lochhamerstrasse 11, 82152 Martinsried, Germany.
Elliott
G
G
Navé
B T
BT
Verzaal
P
P
Rohrbach
M
M
Das
P K
PK
Nagelkerken
L
L
Nieland
J D
JD
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004852:Epoxy Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D010084:Oxidation-Reduction / Q000187:drug effects; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000201:enzymology; D016038:Skin Transplantation; D014183:Transplantation, Heterologous
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir