Effects of 17-beta estradiol and estriol on NMDA-induced toxicity and apoptosis in primary cultures of rat cortical neurons

Estrogens possess neuroprotective and antiapoptotic properties, however, th e issue of involvement of estrogen receptors (ER)-dependent genomic pathway in these effects still remains controversial. Moreover, the majority of da ta on antiapoptotic effects of estrogens concern non-neuronal cells. In the present study we compared effects of the potent ER agonist, estradiol-17 b eta (E2), and its metabolite with a weak affinity for ER, estriol, on the n eurotoxicity induced by high (1 and 5 mM) NMDA concentrations and on the ap optosis induced by low (0.1 mM) concentration of NMDA in rat primary cortic al neurons. The obtained data showed that 24-hour exposure of cortical neur ons to NMDA (0.1-5 mM) resulted in a dose-dependent increase in LDH level. Twenty four-hour pretreatment with estriol (100 nM and 500 nM) reduced the NMDA (I and 5 mM)-induced toxicity by 16-26%, while estradiol-17 beta (500 nM) reduced NMDA (5 mM) - induced toxicity by 14%. Twenty four hour exposur e of cortical neurons to NMDA (0.1 mM) resulted in decrease of the level of antiapoptotic protein - Bcl-2 by 60% and increased the number of apoptotic cells by 50% compared to the control. Twenty four hour pretreatment with e stradiol-17 beta or estriol (100 and 1000 nM) prevented the NMDA-induced ap optotic changes. The specific estrogen receptor antagonist ICI 182,780 (100 nM) had no effect alone and did not antagonize the effects of estrogens on NMDA-induced toxicity as well as on changes in Bcl-2 level. The higher eff icacy of estriol, together with the fact that the specific ER receptor anta gonist, ICI 182,780, did not inhibit the above-described effects support th e hypothesis about a nongenomic mechanism of the anti-NMDA action of estrog ens.