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The present study was designed to investigate the protective efficacy of eugenol against skin cancer and probe into the mechanistic aspects. Skin tumors were initiated by applying 160 nmol DMBA and promoted by twice weekly applications of 8.5 nmol TPA for 28 wk. All mice developed tumors by 13 wk of promotion. However, in mice pretreated with 30 microL eugenol, no tumors were detected until 8 wk (following anti-initiation protocol) and until 14 wk (following antipromotion protocol) of tumor promotion. PCNA and TUNEL immunohistochemistry of tumors revealed eugenol to ameliorate cell proliferation and elevate apoptosis respectively. The effect of eugenol was assessed on specific stages of carcinogenesis. Initiation with DMBA led to a significant upregulation of p53 expression with a concomitant increase in p21(WAF1) levels in epidermal cells indicating induction of damage to the DNA. However, pretreatment with eugenol led to overexpression of these genes, which probably helped stimulate apoptosis of the initiated cells. To ascertain the molecular mechanisms implicated in the antitumor promoting activity of eugenol, its effect was investigated on markers of tumor promotion and inflammation: ODC activity and iNOS and COX-2 expression, and on levels of proinflammatory cytokines (IL-6, TNF-alpha, and PGE(2)). Eugenol markedly inhibited all. Eugenol also inhibited the upstream signaling molecule: NF-kappaB, which regulates the expression of these genes. TPA-induced depletion of cutaneous GSH and antioxidant enzymes armory was also precluded by eugenol. From these results, it could be concluded that eugenol markedly protects against chemically induced skin cancer and acts possibly by virtue of its antiproliferative, anti-inflammatory, and antioxidant activities.

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This study examined the effects of neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and progesterone on the Porsolt forced swim test of depression in mice, and investigated the possible involvement of delta receptors. The immobility time in the mouse forced swimming test was significantly reduced by DHEAS (5 and 20 mg/kg, s.c.) and PS (5 mg/kg) without accompanying changes in the ambulatory or open-field activity. Pretreatment with DHEAS (10 mg/kg) or PS (10 and 20 mg/kg), however, failed to modify the immobility. The relief of behavioral despair in the immobility test by DHEAS (5 and 20 mg/kg) was dose-dependently blocked by preadministration of NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl-ethylamine monohydrochloride; 0.5 and 1 mg/kg), a putative delta1 receptor antagonist, or progesterone (10 mg/kg), a delta receptor antagonistic neurosteroid. On the other hand, PS (5 mg/kg)-induced decrease in the immobility was significantly blocked by NE-100(0.5 mg/kg), but not by progesterone (10 mg/kg). Neither NE-100 nor progesterone influenced the immobility alone. These data suggest a role for central delta receptor in the antidepressant-like effects of neurosteroids, and reinforced their potential therapeutic use in depression.