Studies have reported the protective effect of estradiol (E2) against neuronal death induced by several insults including oxygen deprivation, mitochondrial toxins and activation of glutamate receptors. Glucose deprivation (GD) is associated with ischemia and hypoglycemia, and to date there is no effective therapeutic agent able to prevent neuronal damage induced by these conditions. In this study, we have investigated the effects of 17β-E2 and the selective agonists of the alpha (ERα) and beta (ERβ) estrogen receptors, propyl pyrazole triol (PPT) and diarylpropionitrile (DPN), respectively, on neuronal death induced by GD in cultured rat hippocampal neurons. We have also analyzed the expression of both ER isoforms after GD. Results show that GD for 2 and 4 h reduces cell survival by 42 and 55%, respectively. Treatment with 17β-E2 (10 nM to 10 µM) induces a dose-dependent protective effect that is blocked by ICI 182,780, an ER antagonist, and by 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(-piperidinylethoxy)phenol]-1H′pyrazole dihydrochloride (MPP) and 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), selective ERα and ERβ antagonists, respectively. The ERα and ERβ agonists PPT and DPN show a similar neuroprotective effect to that of 17β-E2, but DPN is more efficient. In addition, hippocampal neurons under normal conditions show a higher expression of the ERβ isoform. When exposed to GD during 4 h, the expression of both ER isoforms is increased, while only that of the ERβ isoform significantly increases after 2 h of GD. Results demonstrate that E2 prevents neuronal death induced by GD through its interaction with ER, although the ERβ isoform might have a predominant role. Results also suggest that GD differentially alters the expression of ERα and ERβ in hippocampal neurons.

Keywords:
Estradiol, Hippocampus, Glucose deprivation, Neuronal death, Neuroprotection, Estrogen receptors
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