The lazaroid tirilazad is a new inhibitor of direct and indirect UVA-induced lipid peroxidation in human dermal fibroblasts

Abstract

Lipid peroxidation caused by oxidative stress within the tissue leads to destruction and dysfunction of cellular membranes. Human dermal fibroblasts in the skin are subject to constant photooxidative stress caused mainly by deeply penetrating UVA irradiation. Therefore, the membrane damage caused by this photooxidative stress may be a major promoter of photoaging and photocarcinogenic processes initiated and promoted by long-term UVA exposure of the skin. The oxidative destruction is counterbalanced by a complex network of enzymatic and nonenzymatic antioxidants creating the skin's line of defence against UVA-induced reactive oxygen species. The lazaroid tirilazad represents a new synthetic group of antioxidants with structural molecular similarity to glucocorticosteroids. We investigated the antioxidative capacity of tirilazad by determining its effects on the levels of malondialdehyde (MDA), as a marker of lipid peroxidation, induced directly or indirectly by UVA in human dermal fibroblasts. In a time- and dose-dependent kinetic, we demonstrated that fibroblasts incubated with tirilazad are well protected against subsequent UVA irradiation and show no increase in MDA levels similar to the unirradiated controls. This was also observed when lipid peroxidation was caused chemically by incubation of human dermal fibroblasts with 200 micro M Fe(3+)-citrate and 1 m M ascorbyl phosphate as a model of indirect UVA-induced skin damage. Lysates of fibroblasts treated this way showed a tenfold increase in MDA levels, whereas preincubation with tirilazad resulted in a significantly lower increase in MDA levels. Furthermore, in a comparison with the well-established radical scavenger Trolox, an alpha-tocopherol analogue, tirilazad offered better protection to the membranes. Our results demonstrate for the first time that the lazaroid tirilazad is an effective inhibitor of direct and indirect UVA-induced increases in MDA as a marker of lipid peroxidation in human dermal fibroblasts.

Nitroxides and a nitroxide-based UV filter have the potential to photoprotect UVA-irradiated human skin fibroblasts against oxidative damage

“…A concentration of 50 mM was chosen based on the fact that this is within the concentration range of compounds normally tested on fibroblasts [25][26][27]. Using the MTT assay, the viability of the cells treated with these compounds at 50 mM did not differ from that of the control (p > 0.05) (data not shown).…”

Glucocorticoids in the treatment of rheumatic diseases: An update on the mechanisms of action

“…These findings stimulated the development of a group of glucocorticoid analogs, the 21‐aminosteroids (lazaroids), that specifically inhibit lipid peroxidation without glucocorticoid or mineralocorticoid activity, thereby avoiding the complications of GC therapy (42, 59). One representative of this class of drugs, tirilazad, has been shown to be neuroprotective (60) and to inhibit ultraviolet A–induced lipid peroxidation in human dermal fibroblasts (61). This drug is generally well tolerated; adverse reactions (such as local discomfort at the site of infusion and physical signs of local venous irritation), although commonly observed, are usually mild and transient.…”