Estrogens with an intact phenolic group prevent death of neuronal cells following glutathione depletion

Oxidative stress-induced neurodegeneration has been implicated in a variety of neuropsychiatric disorders including Alzheimer's disease (AD). Therefor e, neuroprotection is of central interest in basic and preclinical neurosci ence. Recently, we reported that the AD-associated amyloid beta protein can induce neuronal cell death via the generation of free radicals, oxidative stress and lipid peroxidation. The depletion of the intracellular pool of g lutathione (GSH), an important intracellular antioxidant, can also induce o xidative events. Various lipophilic antioxidants, including the female sex hormone estrogen, can protect neurons against oxidative cell death. Here, w e report that estrogens prevent oxidative cell death induced by GSH depleti on in murine clonal hippocampal HT22 cells and in cells of the sympathetic precursor-like cell line PC12. Estrogens act as free radical scavengers and inhibit the intracellular accumulation of peroxides caused by GSH depletio n and, ultimately, prevent neuronal cell death. This protective activity is independent of the presence or activation of estrogen receptors but is dep endent on the presence of an intact hydroxyl group in the steroid ring A of the estrogen molecule. The modification or the absence of this group led t o a loss of the neuroprotective activity. These data further support the im portant role of antioxidants in neuroprotection and may help in the design of novel antioxidant drugs.