Protection of neurons - glutathione as a key mediator for survival with potential implication for use of estrogens as neuroprotectors

Estrogens are regarded as neuroprotectors, but effects by estrogens may be either beneficial or harmful. This thesis suggests that estradiol analogs have the potential as neuroprotectors and that the endogenous antioxidant glutathione is a mediator for survival. The findings were that 17α-estradiol, a stereoisomer of the natural estrogen 17β-estradiol, protects against serum deprivation-induced cell death in the rat pheochromocytoma cell line PC12 in low concentration (1 nM), but not in high concentration (10 µM). The loss of protection at 10 µM was linked to reduced glutathione synthesis and reduction in glutathione levels. On the other hand, the estradiol analogs and G36 (antagonist on the G coupled-protein receptor) did not interfere with glutathione at 10 µM. We also revealed that 10 µM 17α-estradiol, but not 1 nM was neuroprotective against glutamate-induced toxicity when administrated together with glutamate in cerebellar granule neurons from chicken. However, a 24 h pretreatment period with 1 nM protected while 10 µM failed to protect against cell death. The results provide new knowledge about the neuroprotective abilities of 17α-estradiol and estrogen analogs