Abstract: Oxidative stress-induced neurodegeneration has been implicated in a
variety of neuropsychiatric disorders including Alzheimer's disease (AD).
Therefore, neuroprotection is of central interest in basic and preclinical
neuroscience. Recently, we reported that the AD-associated amyliod B protein
can induce neuronal cell death via the generation of free radicals, oxidative
stress and lipid peroxidation. The depletion of the intracellular pool of
glutathione (GSH), an important intracellular oxidant, can also induce
oxidative events. Various lipophilic antioxidants, including the female sex
hormone estrogen, can protect neurons against oxidative cell death. Here, we
report that estrogens prevent oxidative cell death induced by GSH depletion 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 depletion
and, ultimately, prevent neuronal cell death. This protective activity is
independent of the presence or activation of estrogen receptors but is
dependent 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 to a
loss of the neuroprotective activity. These data further support the important
role of antioxidants in neuroprotection and may help in the design of novel
antioxidant drugs.
