Estradiol Treatment Increases Viability of Glioma and Neuroblastoma Cells in Vitro

Wang

et al. 2007

Neuroscience Letters

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The present study was undertaken to determine if the neuroprotective effect of 17β-estradiol (E 2 ) when administrated after ischemia is dose-dependent and if the therapeutic window for estrogen can be prolonged. Ischemic injury was induced by permanent middle cerebral artery occlusion (p-MCAO). Administration of E 2 at 30 minutes after ischemia resulted in a reduction in lesion volume. A higher dose of E 2 extended the therapeutic window to 6 hour after cerebral ischemia in 33% of the rats. These findings suggest that postischemic treatment with estrogen affords protection against ischemic damage and that it acts within a clinically useful therapeutic window.

Section: Discussionmentioning

confidence: 99%

“…We initially reported that estrogens cause a dose-dependent protection of SK-N-SH cells under conditions of serum-deprivation [3,26]. Since these initial observations of in vitro neuroprotection with estrogen treatment, there have been several hundred reports describing the neuroprotective effects of estrogens [4,11].…”

Section: Introductionmentioning

confidence: 99%

Dose dependence and therapeutic window for the neuroprotective effects of 17β-estradiol when administered after cerebral ischemia

Wang

et al. 2007

Neuroscience Letters

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“…Similarly, the ability of estrogens to antagonize these glutamate-induced reductions in protein phosphatases suggests that this action is common to estrogen protection in both oxidative stress and excitotoxicity in neurons. In addition, experimental data from various studies have shown not only the ability of estrogen to protect glial cells from various toxins (Bishop and Simpkins, 1994;Haghighat et al, 2004;Takao et al, 2004) but also the mediation of glial cells in estrogen neuroprotection (Sortino et al, 2004;Wynne and Saldanha, 2004). Therefore, it is important to understand the mechanism of estrogen actions in both neurons and glia.…”

Section: Discussionmentioning

confidence: 99%

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

Yi¹,

Chung²,

Pang³

et al. 2005

J. Neurosci.

The signaling pathways that mediate neurodegeneration are complex and involve a balance between phosphorylation and dephosphorylation of signaling and structural proteins. We have shown previously that 17␤-estradiol and its analogs are potent neuroprotectants. The purpose of this study was to delineate the role of protein phosphatases (PPs) in estrogen neuroprotection against oxidative stress and excitotoxicity. HT-22 cells, C6-glioma cells, and primary rat cortical neurons were exposed to the nonspecific serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A at various concentrations in the presence or absence of 17␤-estradiol and/or glutamate. Okadaic acid and calyculin A caused a dose-dependent decrease in cell viability in HT-22, C6-glioma, and primary rat cortical neurons. 17␤-Estradiol did not show protection against neurotoxic concentrations of either okadaic acid or calyculin A in these cells. In the absence of these serine/threonine protein phosphatase inhibitors, 17␤-estradiol attenuated glutamate toxicity. However, in the presence of effective concentrations of these protein phosphatase inhibitors, 17␤-estradiol protection against glutamate toxicity was lost. Furthermore, glutamate treatment in HT-22 cells and primary rat cortical neurons caused a 50% decrease in levels of PP1, PP2A, and PP2B protein, whereas coadministration of 17␤-estradiol with glutamate prevented the decrease in PP1, PP2A, and PP2B levels. These results suggest that 17␤-estradiol may protect cells against glutamate-induced oxidative stress and excitotoxicity by activating a combination of protein phosphatases.

“…Estrogen analogs such as 17␣-estradiol, ENT E2, and ZYC3 (structures in Fig. 1) have been shown to be as potent neuroprotectants as 17␤-estradiol (Bishop and Simpkins, 1994;Green et al, 2001;Perez et al, 2005). To determine the effectiveness of 17␣-estradiol, ENT E2, and ZYC3 to protect neurons against oxidative stress or excitotoxicity induced by glutamate in the presence of a serine/threonine phosphatase inhibitor, we examined simultaneous treatment as well as 2-or 24-h pretreatment of 17␣-estradiol, ENT E2, or ZYC3 with glutamate and/or okadaic acid or calyculin A.…”

Section: Effects Of Pp Inhibitors On Estrogen Analog-mediatedmentioning

confidence: 99%

Estrogen Receptor-Independent Neuroprotection via Protein Phosphatase Preservation and Attenuation of Persistent Extracellular Signal-Regulated Kinase 1/2 Activation

Cai²,

Covey³

et al. 2007

J Pharmacol Exp Ther

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The mechanism of estrogen-mediated neuroprotection is not yet clear. Estrogens have a variety of modes of action, including transducing signaling events such as activation and/or suppression of the mitogen-activated protein kinase (MAPK) pathway. We have previously shown protein phosphatases to be involved in 17␤-estradiol-mediated neuroprotection. In the present study, we assessed the role of estrogen receptors (ERs) in estrogen-mediated neuroprotection from oxidative/excitotoxic stress and the consequential effects on MAPK signaling. Okadaic acid and calyculin A, nonspecific serine/threonine phosphatase inhibitors, were exposed to cells at various concentrations in the presence or absence of 17␣-estradiol, the enantiomer of 17␤-estradiol, 2-(1-adamantyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (ZYC3; non-ER-binding estrogen analog), and/or glutamate. All three compounds, which we have shown to have little or no binding to ER␣ and ER␤, were protective against glutamate toxicity but not against okadaic acid and calyculin A toxicity. In addition, in the presence of effective concentrations of these inhibitors, the protective effects of these estrogen analogs were lost. Glutamate treatment caused a 50% decrease in levels of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A), and protein phosphatase 2B (calcineurin) (PP2B). Coadministration of ZYC3 with glutamate prevented the decreases in PP1, PP2A, and PP2B levels. Furthermore, glutamate treatment caused a persistent increase in phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 that corresponds with the decrease protein levels of serine/threonine phosphatases. ZYC3 blocked this persistent increase in ERK phosphorylation. These results suggest that estrogens protect cells against glutamate-induced oxidative stress through an ER-independent mediated mechanism that serves to preserve phosphatase activity in the face of oxidative insults, resulting in attenuation of the persistent phosphorylation of ERK associated with neuronal death.