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, the issue of involvement of estrogen receptors (ER)-dependent genomic pathway in these effects still remains controversial. Moreover, the majority of data on antiapoptotic effects of estrogens concern non-neuronal cells. In the present study we compared effects of the potent ER agonist, estradiol-17beta (E2), and its metabolite with a weak affinity for ER, estriol, on the neurotoxicity induced by high (1 and 5 mM) NMDA concentrations and on the apoptosis induced by low (0.1 mM) concentration of NMDA in rat primary cortical neurons. The obtained data showed that 24-hour exposure of cortical neurons 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 (1 and 5 mM)-induced toxicity by 16-26%, while estradiol-17beta (500 nM) reduced NMDA (5 mM)- induced toxicity by 14%. Twenty four hour exposure 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 estradiol-17beta or estriol (100 and 1000 nM) prevented the NMDA-induced apoptotic 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 efficacy of estriol, together with the fact that the specific ER receptor antagonist, ICI 182,780, did not inhibit the above-described effects support the hypothesis about a nongenomic mechanism of the anti-NMDA action of estrogens.
Kajta
M
M
Department of Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Cracow.
Budziszewska
B
B
Marszał
M
M
Lasoń
W
W
D000324:Adrenocorticotropic Hormone / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology*; D004964:Estriol / Q000494:pharmacology*; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D051381:Rats
D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D004958:Estradiol; D016202:N-Methylaspartate; D000324:Adrenocorticotropic Hormone; D007770:L-Lactate Dehydrogenase; D004964:Estriol