Reduction of acute photodamage in skin by topical application of a novel PARP inhibitor.
The ultraviolet (UV) components of sunlight induce damage to the DNA in skin cells, which is considered to be the initiating step in the harmful biological effects of UV radiation. Repair of DNA damage results in the formation of single-strand DNA breaks, which activate the nuclear poly(ADP-ribose) polymerase (PARP). Overactivation of PARP worsens the oxidative cell damage and impairs the energy metabolism, raising the possibility that moderation of PARP activation following DNA damage may protect skin cells from UV radiation. The topical effects of the novel PARP inhibitor O-(3-pyperidino-2-hydroxy-1-propyl) pyridine-3-carboxylic acid amidoxime monohydrochloride (BGP-15M) were investigated on UV-induced skin damage in a hairless mouse model. For evaluation of the UV-induced acute photodamage to the skin and the potential protective effect of BGP-15M, DNA injury was detected by measuring the formation of single-strand DNA breaks and counting the resulting sunburn (apoptotic) cells. The ADP-ribosylation of PARP was assessed by Western blot analysis and then quantified. In addition, the UV-induced immunosuppression was investigated by the immunostaining of tumor necrosis factor alpha and interleukin-10 expressions in epidermal cells. The signs of inflammation were examined clinically and histochemically. Besides its primary effect in decreasing the activity of nuclear PARP, topically applied BGP-15M proved to be protective against solar and artificial UV radiation-induced acute skin damage. The DNA injury was decreased (P<0.01). An inhibition of immunosuppression was observed by down-regulation of the epidermal production of cytokines IL-10 and TNFalpha. In the mouse skin, clinical or histological signs of UV-induced inflammation could not be observed. These data suggest that BGP-15M directly interferes with UV-induced cellular processes and modifies the activity of PARP. The effects provided by topical application of the new PARP-regulator BGP-15M indicate that it may be a novel type of agent in photoprotection of the skin.
Farkas
Beatrix
B
Department of Dermatology, Faculty of Medicine, University of Pecs, Kodaly u. 20, H-7624, Pecs, Hungary. farkasb@derma.pote.hu
Magyarlaki
Marta
M
Csete
Bela
B
Nemeth
Jozsef
J
Rabloczky
Gyorgy
G
Bernath
Sandor
S
Literáti Nagy
Peter
P
Sümegi
Balazs
B
D000244:Adenosine Diphosphate / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000378:metabolism / Q000528:radiation effects; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010091:Oximes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010880:Piperidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011855:Radiodermatitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013471:Sunburn / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays
D004277:DNA, Single-Stranded; D010091:Oximes; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000244:Adenosine Diphosphate; C405586:BGP 15