Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K/Akt pathway

Jover‐Mengual, Teresa; Miyawaki, Takahiro; Latuszek, Adrianna; Alborch, Enrique; Zukin, R. Suzanne; Etgen, Anne M.

doi:10.1016/j.brainres.2010.01.046

Cited by 74 publications

(65 citation statements)

References 79 publications

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“…Notably, BI had no effect on neuron count in CA2 and CA3 areas, suggesting that neurons in CA1 are vulnerable to radiation-induced cell damage. This notion is supported by previous studies showing that ischemia caused highly selective delayed cell death in the hippocampal CA1 zone, indicating the general vulnerability of this subgroup of hippocampal neurons [24]. The BI-induced reduction in hippocampal size and decreased neuron count can result in significantly decreased hippocampal GR binding of Dex as shown here.…”

Section: Discussionsupporting

confidence: 77%

Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat Model

Weidenfeld

Siegal

Ovadia

2012

Neuroimmunomodulation

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Background: Brain irradiation (BI) in humans may cause behavioral changes, cognitive impairment and neuroendocrine dysfunction. The effect of BI on the hypothalamic-pituitary-adrenal (HPA) axis is not fully understood. Objectives: To evaluate the effect of BI on HPA axis responses under basal and stressful conditions as well as following pretreatment with dexamethasone (Dex). Methods: Adult male rats were exposed to whole BI. HPA axis responses were examined at 2, 4, 9 and 20 weeks after BI. Histological evaluations of the irradiated rats and matched controls were conducted at 4 and 20 weeks after BI. Results: In contrast to the control group, the basal and stress-induced corticosterone levels were enhanced at 9 and 20 weeks after BI and the inhibitory effect of Dex was reduced. BI also caused hyposuppression of the adrenocortical response to stress. Histological assessment of the irradiated brains revealed hippocampal atrophy at 20 weeks after BI. The neuronal counts were lower only in the CA1 region of the irradiated brains. BI caused a decrease in the binding capacity of Dex to the hippocampal cytosolic fraction. Conclusions: Enhanced stress-induced HPA axis responses and the reduced effect of Dex suggest that BI has delayed effects on HPA axis responses as manifested by impairment of the negative feedback exerted by glucocorticoids (GCs). The mechanisms underlying these effects of BI are unknown. It is possible that the marked BI-induced damage in the hippocampus, which plays an important role in the regulation of the feedback effect of GCs, may cause abnormal HPA axis responses following BI.

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Section: Discussionsupporting

confidence: 77%

Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat Model

Weidenfeld

Siegal

Ovadia

2012

Neuroimmunomodulation

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“…Recent evidence suggests that E2 also exerts "rapid signaling" in the brain via interaction with extranuclear ER, which can lead to regulation of kinase activation and ion channels (17,18). ER "extranuclear" signaling has been suggested to contribute to E2 neuroprotective effects by facilitating the rapid activation of extracellular signal-regulated kinases (ERKs) and prosurvival serine threonine kinase Akt (4,(19)(20)(21)(22). Furthermore, E2 also interacts with nonclassical ERs such as G protein-coupled estrogen receptor, which can also contribute to activation of ERK and PI3K (4,23).…”

mentioning

confidence: 99%

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Sareddy

Zhang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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17-β estradiol (E2) has been implicated as neuroprotective in a variety of neurodegenerative disorders. However, the underlying mechanism remains unknown. Here, we provide genetic evidence, using forebrain-specific knockout (FBKO) mice, that proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), an estrogen receptor coregulator protein, is essential for the extranuclear signaling and neuroprotective actions of E2 in the hippocampal CA1 region after global cerebral ischemia (GCI). E2-mediated extranuclear signaling (including activation of extracellular signal-regulated kinase and Akt) and antiapoptotic effects [such as attenuation of JNK signaling and increase in phosphorylation of glycogen synthase kinase-3β (GSK3β)] after GCI were compromised in PELP1 FBKO mice. Mechanistic studies revealed that PELP1 interacts with GSK3β, E2 modulates interaction of PELP1 with GSK3β, and PELP1 is a novel substrate for GSK3β. RNA-seq analysis of control and PELP1 FBKO mice after ischemia demonstrated alterations in several genes related to inflammation, metabolism, and survival in PELP1 FBKO mice, as well as a significant reduction in the activation of the Wnt/ β-catenin signaling pathway. In addition, PELP1 FBKO studies revealed that PELP1 is required for E2-mediated neuroprotection and for E2-mediated preservation of cognitive function after GCI. Collectively, our data provide the first direct in vivo evidence, to our knowledge, of an essential role for PELP1 in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.he steroid hormone, 17β-estradiol (E2), exerts multiple actions in the brain, including regulation of synaptic plasticity, neurogenesis, reproductive behavior, and cognition. E2 has also been implicated to serve as an important neuroprotective factor in a variety of neurodegenerative disorders, including stroke and Alzheimer's disease (1-3). The main source of E2 synthesis in females is the ovary. Circulating E2 levels are known to fluctuate during development and puberty, as well as during the menstrual cycle. After menopause, however, circulating E2 levels decline precipitously (4). Relative to men, women are "protected" against stroke until the years of menopause. However, after menopause, women exhibit a significantly higher disability and fatality rate compared with men (5-7). Intriguingly, the higher risk and poorer outcome of stroke in postmenopausal women parallels the falling E2 levels that occur after menopause (7,8). Furthermore, exogenous administration of E2 significantly reduces the infarct volume in cortex and hippocampus after focal and global cerebral ischemia (GCI) in various animal models, and female animals exhibit reduced neural damage compared with young adult males after brain injury (1, 9-11). Taken as a whole, these studies suggest E2 functions as an important neuroprotective factor. However, the molecular mechanisms by which E2 exerts its neuroprotective effects remain unclear.E2 signaling is thought to be primarily mediated by the classical...

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“…Besides, the opportunity time window may be further extended when it is expected that neuroprotective procedures act through promotion of cellular processes of neuronal repair and plasticity. In view of the multiple pathophysiological processes occurring both in sequence and simultaneously after ischemia and reperfusion, it is considered as an advantage for presumptive neuroprotective drugs to have multiple cellular or molecular mechanisms of action, as occurring with some originally endogenous compounds, namely melatonin, estradiol and progesterone (El-Abhar et al, 2002;Hurn et al, 1995;Jover-Mengual et al, 2010;Lebesgue et al, 2009;Reiter et al, 2005;Wang et al, 2008). By contrast, most synthetic drugs only have one mechanism of action accounting for neuroprotection.…”

Section: Approaches To Neuroprotection In Animal Models Of Global Cermentioning

confidence: 99%

Neuroprotection in Animal Models of Global Cerebral Ischemia

Cervantes¹,

González-Burgos²,

Letechipía-Vallejo³

et al. 2012

Advances in the Preclinical Study of Ischemic Stroke

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Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K/Akt pathway

Cited by 74 publications

References 79 publications

Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat Model

Delayed Effects of Brain Irradiation – Part 1: Adrenocortical Axis Dysfunction and Hippocampal Damage in an Adult Rat Model

Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain

Neuroprotection in Animal Models of Global Cerebral Ischemia

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