Hormetic mechanism of ebselen: A general mechanistic hypothesis

• Ebselen promotes adaptation at low doses and cytotoxicity at high doses, hence a hormetic effect • The main effect of ebselen appears to be to induce redox stress by decreasing the GSH/GSSG. • The protective adaptation in response to ebselen-induced redox stress is orchestrated by NRF-2 activation. Ebselen is a small organic molecule developed as a mimetic of the antioxidant enzyme GPx. Ebselen has been extensively studied in cellular models, animals and is now in clinical trials to treat several pathological conditions in which oxidative stress is the predominant factor. Many of the positive results of ebselen treatment have been attributed to its role as a direct antioxidant. However, there is evidence of cytotoxic activity of ebselen, mostly explored in cancer cells, bacteria and fungi. Based on previous results and ongoing research, our mechanistic proposal is that at low doses ebselen behaves as a hormetic compound via its GPx mimetic activity, initially depleting reduced GSH levels, creating a redox stress that leads to an adaptive response orchestrated by NRF-2. The net result would be a more robust antioxidant profile, hence the protective effect. On the other hand, at high doses, the redox stress exceeds the cellular adaptive capacity and leads to apoptosis, probably via the mitochondrial pathway. Thus, our mechanistic proposal has the potential to reconcile several results present in the literature that often seem contradictory. Since ebselen is currently being tested in several phase 1, phase 2 and phase 3 clinical trials, in addition to having already shown positive clinical results, our mechanistic proposal has the potential to provide support for the development of treatment protocols that are more effective in the pathological conditions that can benefit from the effects promoted ebselen’s hormetic effect.