Currently, there is no effective
antidote to prevent skin
injuries by
sulfur mustard (SM) and
nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of
silibinin, a natural
flavanone, in reversing monofunctional alkylating SM analog
2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating
vesicant, herein, efficacy studies were carried out with NM. Topical application of
silibinin (1 or 2mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically,
silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis,
parakeratosis and microvesication. Higher
silibinin dose also caused a 79% and 51%reversal in NM-induced increases in
myeloperoxidase activity and COX-2 levels, respectively. Furthermore,
silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of
8-oxodG in NM-exposed mouse skin that was significantly reversed by
silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by
silibinin is due to its effects on the pathways associated with DNA damage,
inflammation,
vesication and oxidative stress. In conclusion, results presented here support the optimization of
silibinin as an effective treatment of skin injury by
vesicants.