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Pro-rich antimicrobial peptides are a group of linear peptides of innate immunity isolated from mammals and invertebrates, and characterised by a high content of proline residues (up to 50%). Members of this group are predominantly active against Gram-negative bacterial species which they kill by a non-lytic mechanism, at variance with the majority of the known antimicrobial peptides. Evidence is accumulating that the Pro-rich peptides enter the cells without membrane lysis and, once in the cytoplasm, bind to, and inhibit the activity of specific molecular targets essential to bacterial growth, thereby causing cell death. This mode of action makes these peptides suitable for drug development efforts. In addition to antibacterial action, PR-39, one of the better characterised Pro-rich peptides from mammals, exerts other potentially exploitable biological activities, such as induction of syndecan expression in mesenchymal cells and inhibition of the NADPH oxidase activity of neutrophils, suggesting a role of this peptide in wound repair and inflammation. PR-39 also exerts a protective effect in various animal models of ischemia-reperfusion injury, preventing the post-ischemic oxidant production, and is a potent inducer of angiogenesis both in vitro and in vivo. Although the physiological relevance of all these effects has not yet been established, the above observations underscore the therapeutic potential of this peptide in a number of complex processes such as inflammation, wound repair, ischemia-reperfusion injury, and angiogenesis.

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Topically applied antioxidants constitute an important group of protective agents against skin damage induced by ultraviolet radiation. The current study was performed to investigate whether a recently developed ex vivo pig skin model was suitable for short-term studies of the mechanism(s) of UVB-radiation-induced skin damage; the protective effect of topical application of alpha-tocopherol, l-ascorbic acid, alpha-lipoic acid, glutathione ethylester and N-acetylcysteine was tested. Increasing doses of the antioxidants were applied topically on ex vivo pig skin explants and allowed to penetrate for 60 min. Epidermal antioxidant bioavailability was measured before and 60 min after exposure to an ultraviolet B (UVB) radiation of 7.5 kJ/m2. Cell viability (trypan blue dye exclusion) and apoptosis were measured 48 h later in isolated keratinocytes. UVB-radiation-induced epidermal lipid peroxidation was determined immediately after exposure of the skin to a UVB dose of 28 kJ/m2. All antioxidants tested became bioavailable in pig skin epidermis, and none of them were depleted after UVB-radiation exposure. Increasing doses of the antioxidants tested decreased UVB-radiation-induced cell death and apoptosis. The highest doses of antioxidants prevented UVB-radiation-induced lipid peroxidation; alpha-lipoic acid only tended to decrease lipid peroxidation. In conclusion, a single topical dose of the above antioxidants on ex vivo pig skin can reduce UVB-radiation-induced oxidative stress and lipid peroxidation and thereby reduce apoptotic stimuli and cell death. Furthermore, the ex vivo pig skin model was a useful tool for testing compounds for their antioxidant activity.

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Exposure of the nonsteroidal anti-inflammatory drug suprofen (SUP) to UV-radiation results in the formation of radicals, reactive oxygen species (ROS), photodecarboxylated products and photoadducts with biomacromolecules. Using an ex vivo pigskin explant model, we investigated whether topical coapplication of the water-soluble antioxidants vitamin C (Lascorbic acid, ASC), N-acetyl-L-cysteine (NAC) or L-cysteine ethylester (CYSET) with SUP reduced ultraviolet A (UVA)-induced decomposition of SUP. UVA-induced changes in antioxidant bioavailability in the stratum corneum and epidermis were also studied. Epidermal bioavailability of SUP in sham-irradiated pigskin increased 2.2- to 4.1-fold after the lowest antioxidant doses (P < 0.05). As compared with no applied antioxidant, increasing doses of all tested antioxidants resulted in increased levels of SUP and decreased levels of photoproducts (P < 0.05). A maximal protection against SUP photodegradation of 70% was found after an ASC dose of 1 micromol/cm2; these values were 60% for a NAC dose of 10 micromol/cm2 and 50% for a CYSET dose of 5 micromol/cm2. Skin antioxidant levels increased with increasing applied dose (P < 0.05); the bioavailability of CYSET was approximately three-fold lower than that of ASC and NAC. UVA exposure resulted in 30-50% consumption of the topically applied ASC or NAC in the stratum corneum, whereas CYSET was not consumed. In conclusion, the topically applied water-soluble antioxidants ASC, NAC and CYSET protect against UVA-induced decomposition of SUP by scavenging radicals and ROS. Coapplication of these antioxidants may therefore be an effective way to reduce or prevent the phototoxic effects of SUP in vivo.

Exposure of the nonsteroidal anti‐inflammatory drug suprofen (SUP) to UV‐radiation results in the formation of radicals, reactive oxygen species (ROS), photodecarboxylated products and photoadducts with biomacromolecules. Using an ex vivo pigskin explant model, we investigated whether topical coapplication of the water‐soluble antioxidants vitamin C (l‐ascorbic acid, ASC), N‐acetyl‐l‐cysteine (NAC) or l‐cysteine ethylester (CYSET) with SUP reduced ultraviolet A (UVA)‐induced decomposition of SUP. UVA‐induced changes in antioxidant bioavailability in the stratum corneum and epidermis were also studied. Epidermal bioavailability of SUP in sham‐irradiated pigskin increased 2.2‐ to 4.1‐fold after the lowest antioxidant doses (P < 0.05). As compared with no applied antioxidant, increasing doses of all tested antioxidants resulted in increased levels of SUP and decreased levels of photoproducts (P < 0.05). A maximal protection against SUP photodegradation of 70% was found after an ASC dose of 1 μmol/cm2; these values were 60% for a NAC dose of 10 μmol/cm2 and 50% for a CYSET dose of 5 μmol/cm2. Skin antioxidant levels increased with increasing applied dose (P < 0.05); the bioavailability of CYSET was approximately three‐fold lower than that of ASC and NAC. UVA exposure resulted in 30–50% consumption of the topically applied ASC or NAC in the stratum corneum, whereas CYSET was not consumed. In conclusion, the topically applied water‐soluble antioxidants ASC, NAC and CYSET protect against UVA‐induced decomposition of SUP by scavenging radicals and ROS. Coapplication of these antioxidants may therefore be an effective way to reduce or prevent the phototoxic effects of SUP in vivo.