Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-β.

While both 17β-estradiol (E2) and progesterone (P4) are neuroprotective in several experimental paradigms, P4 also counteracts E2 neuroprotective effects. We recently reported that a 4-h treatment of cultured hippocampal slices with P4 following a prolonged (20 h) treatment with E2 eliminated estrogenic neuroprotection against NMDA toxicity and induction of brain-derived neurotrophic factor (BDNF) expression. In the present study, we evaluated the effects of the same treatment on levels of estrogen receptors, ERα and ERβ, and BDNF using a similar paradigm. E2 treatment resulted in elevated ERβ mRNA and protein levels, did not modify ERα mRNA, but increased ERα protein levels, and increased BDNF mRNA levels. P4 reversed E2-elicited increases in ERβ mRNA and protein levels, in ERα protein levels, and in BDNF mRNA levels. Experiments with an ERβ-specific antagonist, PHTPP, and specific agonists of ERα and ERβ, propylpyrazoletriol and diarylpropionitrile, respectively, indicated that E2-mediated neuroprotection against NMDA toxicity was, at least in part, mediated via ERβ receptor. In support of this conclusion, E2 did not protect against NMDA toxicity in cultured hippocampal slices from ERβ-/- mice. Thus, E2-mediated neuroprotection against NMDA toxicity may be because of estrogenic induction of BDNF via its ERβ receptor, and P4-mediated inhibition of E2 neuroprotective effects treatment to P4-induced down-regulation of ERβ and BDNF.