Estradiol Protects Against Oxygen and Glucose Deprivation in Rat Hippocampal Organotypic Cultures and Activates Akt and Inactivates GSK-3?

Abstract

Here we investigated the neuroprotective effect of 17beta-estradiol in an in vitro model of ischemia. We used organotypic hippocampal slice cultures, acute or chronically treated with 17beta-estradiol (10 nM), and exposed to oxygen and glucose deprivation (OGD). Cellular death was quantified by measuring uptake of propidium iodide (PI), a marker of dead cells. In OGD exposed cultures, treated only with vehicle, about 70% of the CA1 area of hippocampus was labeled with PI, indicating a great percentage of cellular death. When cultures were treated with 17beta-estradiol (acute or chronically), this cellular death was reduced to 15%. This effect was prevented by LY294002 but was not by PD98059. Immunoblotting revealed that both, chronic and acute, treatments with 17beta-estradiol induced the phosphorylation/activation of Akt and the phosphorylation/inactivation of GSK-3beta. Our results show a clear neuroprotective effect of 17beta-estradiol and suggest that this effect could involve PI3-K pathway.

Hypothermia blocks β-catenin degradation after focal ischemia in rats

“…We have previously reported that hypothermia blocks ischemic injury without inhibiting increased-GSK3β activity [14]; this result contradicts with the earlier results showing that GSK3β activity leads to neuronal death [2,6,8]. In our prior study, however, hypothermia blocks nuclear translocation of β-catenin [14], suggesting that hypothermia may block molecular signaling downstream of GSK3β.…”

“…Moderate hypothermia attenuates reductions in Akt activity after stroke [14] but does not attenuate reduction in GSK 3 β phosphorylation, suggesting that it may not inhibit GSK3β activity [14]. Since GSK3β activity is known to exacerbate ischemic injury, and its inhibition reduces infarction [2,6,8], it is puzzling that hypothermia can inhibit ischemic injury without blocking GSK 3 β activity. To address this paradox, we further examined the protective effects of moderate hypothermia on β-catenin phosphorylation and total protein level of β-catenin (molecules downstream of GSK3β), in the same focal ischemia model with rats we used before for studying the Akt/GSK3β pathway.…”

Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity

“…Estrogens are neuroprotective in a variety of cellular and animal models, including cell cultures challenged with excitotoxins or other insults (Goodman et al, 1996;Singer et al, 1999;Harms et al, 2001;Cimarosti et al, 2005), models of focal or global brain ischemia (Simpkins et al, 1997;Dubal et al, 1998;Lebesgue et al, 2009), mice treated with the parkinsonian toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Bourque et al, 2009), and transgenic mice carrying mutations associated with Alzheimer's disease (Carroll et al, 2007;Amtul et al, 2010). Estrogens are also effective in reducing ␤-amyloid toxicity in cultured neurons (Goodman et al, 1996;Chae et al, 2001;Marin et al, 2003;Sortino et al, 2004;Cordey and Pike, 2005), an established cellular model of Alzheimer's disease.…”

“…In addition, a G protein-coupled receptor, GPR30, has been identified as an additional candidate membrane ER (Revankar et al, 2005;Thomas et al, 2005) and reported to also mediate estrogen neuroprotective effects against excitotoxicity (Gingerich et al, 2010). Membrane ERs trigger a variety of putative neuroprotective pathways, which include the mitogen-activated protein kinase (MAPK) pathway (Singer et al, 1999;Mize et al, 2003) and the phosphatidylinositol 3-kinase (PtdIns-3-K)/Akt pathway (Honda et al, 2000;Harms et al, 2001;Cimarosti et al, 2005). The mechanism whereby membrane ERs activate the neuroprotective cascade is largely unknown.…”

Inmunohistochemical Evaluation of Estrogen Receptors Alpha and Beta in Normal Inferior Turbinate Mucosa

“…A large number of clinical conditions are associated with changes in estrogen production or hormonal cell response, such as osteoporosis, atherosclerosis and breast, endometrial and prostate cancer (Enmark & Gustafson, 1999). In the central nervous system, estrogen is considered to be a neuroprotection agent against cerebral ischemia (Cimarosti, 2005). Moreover, this hormone is also known to have a role in modulating neurogenic inflammatory reactions (Bjorling & Wang, 2001).…”