Melatonin Ameliorates Doxorubicin-induced Skin Necrosis in Rats

Abstract

Doxorubicin (DXR), a highly effective chemotherapeutic agent, causes serious injury when extravasated. The injury can sometimes result in skin necrosis and ulceration, requiring surgery. The detrimental effect of DXR on the antioxidant system via free oxygen radicals is one of the mechanisms proposed in its etiology. Thus, we used melatonin, a potent antioxidant, and compared the effects with dimethylsulfoxide (DMSO), which is used in the treatment of patients with DXR-induced extravasation.Twenty-seven Wistar-albino rats were used. After intradermal injection of DXR, DMSO was injected into the extravasated area and melatonin was given intraperitoneally. On day 14 of the experiment, skin ulcers were clearly formed and samples were taken with a punch biopsy. Ulcer sizes were measured. Tissue samples were analyzed for superoxide dismutase, glutathione peroxidase, and malondialdehyde enzymes, and histopathologically evaluated.Melatonin clearly decreased MDA levels, ulcer size, and histopathologic ulcer scores in DXR extravasated tissue. DMSO also decreased MDA levels, ulcer size and histopathologic ulcer score. However, melatonin was remarkably more effective than DMSO in terms of antioxidant enzyme activity, oxidative stress, and histopathologic ulcer scores in rats. Necrosis was evident in the DXR-treated group and some slides showed necrosis involving the fascia. Histopathologic ulcer scores of the necrotic tissue decreased in the DMSO and melatonin groups. The ulcer score in the melatonin group was significantly lower than in the control group. Although the ulcer score in the DMSO group was lower than control, there was no statistically significant difference. The ulcer size in the DMSO group was significantly lower than the control group. The ulcer size in the melatonin group was significantly lower than both the DMSO and control groups.We believe that melatonin, either alone or in combination with DMSO, may be used for treating DXR extravasation. In addition, free oxygen radicals play a crucial role in the etiology of the injury, which should be considered in further studies.