We compared the neuroprotective effects of the catecholestrogen 2-hydroxy-estradiol (2-OH-E(2)) to the actions of 17-beta-estradiol (E(2)), since catecholestrogens have been clinically implicated in the pathophysiology of major depression and other psychiatric diseases. Using the hippocampal HT22 cell line as a well-established in vitro model system, we here show that the extent of the neuroprotective effects of 2-OH-E(2) was significantly increased compared to the physiological estrogen E(2) at equimolar concentrations after a toxic challenge with hydrogen peroxide. Statistically significant effects of neuroprotection as measured by survival of HT22 cells were detectable at concentrations of 1 and 10 microM of 2-OH-E(2) or E(2). Studies on the time-dependence of the evoked reactions showed that a pre-incubation and a post-incubation up to 30 min with a dose of 10 microM of 2-OH-E(2) resulted in a significant decrease in cell death after incubation with hydrogen peroxide if compared to E(2). Further characterization of the effects in rat brain homogenates with an assay for the induction of cellular lipid peroxidation (LPO) revealed, that 2-OH-E(2) was more effective in the reduction of LPO than E(2) in equimolar concentrations. This indicates a pharmacologically relevant effect of this hormone metabolite and a mechanism of action, which does not involve the classical estrogen receptor. In conclusion, the catecholestrogen 2-OH-E(2) induces increased neuroprotective actions in comparison to the major physiological estrogen E(2), suggesting a clinically relevant physiological function of catecholestrogens during health and disease.