Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies

Wise, Phyllis M.; Dubal, Dena B.; Wilson, Melinda E.; Rau, Shane W.; Böttner, Martina; Rosewell, Katherine L.

doi:10.1016/s0165-0173(01)00136-9

Cited by 199 publications

(146 citation statements)

References 43 publications

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“…A primary ovarian hormone, estrogen has been associated with the sex difference in ischemic stroke as treatment of estrogen in the male or ovariectomized animals reduced infarct and neuronal death following ischemia [177][178][179][180]. The neuroprotective effect of estrogen is related to anti-inflammation in young but proinflammation in the aged brain [181][182][183][184], reduced microglial proliferation, attenuated macrophage cytokine production, and recruitment of macrophages in ischemic injury [185]. Accordingly, reduced CD45 hi /CD11b + cells (activated microglia and infiltrated macrophages) in the brain and fewer spleen contractions have been related to the smaller injury in females [166].…”

Section: Sex-associated Modulation Of Mononuclear Phagocytesmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

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Section: Sex-associated Modulation Of Mononuclear Phagocytesmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

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“…Regan and Guo, 1997). An emerging concept is that neuroprotection afforded by estrogens is ER-mediated at low physiological concentrations of the steroid, but ER-independent at pharmacological concentrations of estrogens Simpkins, 2000a, 2000b;Wise et al, 2001;McEwen, 2001). …”

Section: Estrogens and Neuroprotectionmentioning

confidence: 99%

Estrogen actions on mitochondria—Physiological and pathological implications

Simpkins

Yang

Sarkar

et al. 2008

Molecular and Cellular Endocrinology

132

105

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Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and other have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor β (ERβ) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERβ is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERβ can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

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“…N eurologic benefits of estrogen replacement therapy in humans include reversal of estrogen deficiency-induced memory dysfunction and reduced risk of Alzheimer's disease (AD) (1)(2)(3)(4)(5). Recently, the Cache County Study confirmed a reduced risk of AD in elderly women on hormone replacement therapy (HRT) (6).…”

mentioning

confidence: 99%

“…Estrogen-induced neuroprotection against excitotoxic glutamate is correlated with an attenuated rise in intracellular calcium concentration ([Ca 2ϩ ] i ) (17,18). Thus, we sought to determine the impact of P 4 and MPA on excitotoxic glutamate-induced [Ca 2ϩ ] i rise. Here we show that E 2 and P 4 attenuated the glutamate-induced rise in [Ca 2ϩ ] i .…”

mentioning

confidence: 99%

Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling

Nilsen

Brinton

2003

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

226

157

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The impact of progestins on estrogen-inducible mechanisms of neuroprotection was investigated. Previously, we showed that estrogen and progesterone are neuroprotective against excitotoxicity, whereas the synthetic progestin medroxyprogesterone acetate (MPA; Provera) is not. Here, we demonstrate that 17␤-estradiol (E 2) and progesterone (P4) treatment of hippocampal neurons attenuated the excitotoxic glutamate-induced rise in intracellular calcium concentration. Although MPA had no effect alone, MPA completely antagonized E 2-induced attenuation of intracellular calcium concentration. Activation of extracellular receptor kinase (ERK) is required for estrogen-induced neuroprotection and calcium regulation. Paradoxically, E 2, P4, and MPA all elicited similar rapid and transient activation of ERK, presenting a contradiction between the dependence on ERK for gonadal hormone-induced neuroprotection and the lack of neuroprotection induced by MPA. Subcellular analysis of ERK demonstrated that the phospho-ERK signal is transduced to the nucleus only by E 2 and P4, not by MPA. These results indicate that the profile of nuclear translocation of ERK is consistent with the neuroprotective profile. Further, the E 2-induced nuclear translocation of ERK was blocked by coadministration of MPA. Results of this study reveal that nuclear ERK induction by ovarian steroids is predictive of the neuroprotective effects of estrogen and progestin treatments, revealing a hitherto unrecognized divergence of progestin signaling through the src͞ MAPK pathway. These results have much broader implications encompassing the impact of progestins on estrogen-mediated effects in multiple tissues. The recent results from the Women's Health Initiative trial, which used MPA as the progestinal agent, indicate that differences between progestin formulations are crucial to health outcomes in women.N eurologic benefits of estrogen replacement therapy in humans include reversal of estrogen deficiency-induced memory dysfunction and reduced risk of Alzheimer's disease (AD) (1-5). Recently, the Cache County Study confirmed a reduced risk of AD in elderly women on hormone replacement therapy (HRT) (6). Because progestins are added to HRT to prevent hyperplasia of the endometrium (7) and resulting uterine cancer (8), possible impacts of progestins need to be determined. Numerous studies have found contradictory effects of estrogen͞ progestin use and breast cancer (9), coronary heart disease (10), and cognition (11,12). Although some of these studies used the same hormone formulation [conjugated estrogens (Premarin) with medroxyprogesterone acetate (MPA; Provera)], many did not determine or subdivide the type of progestin used (9-14), raising the possibility that the apparent discrepancies in outcomes are due to the differences in cellular responses induced by different progestins. Such concerns have been underscored by the termination of the combined regimen arm of the Women's Health Initiative trial (11,12,15).In earlier work, we found that 17␤-estradiol (E 2...

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Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivo and in vitro studies

Cited by 199 publications

References 43 publications

Microglia and Monocyte-Derived Macrophages in Stroke

Microglia and Monocyte-Derived Macrophages in Stroke

Estrogen actions on mitochondria—Physiological and pathological implications

Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling

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