The female sex hormone oestrogen as a neuroprotectant

doi:10.1016/S0165-6147(99)01392-9

Trends in Pharmacological Sciences

Volume 20, Issue 11, 1 November 1999, Pages 441-444

https://doi.org/10.1016/S0165-6147(99)01392-9 Get rights and content

Abstract

It is well recognized that oestrogen regulates sex differentiation and maturation of sex organs via binding to specific intracellular receptors. However, oestrogen receptors (ERs) are expressed in a variety of other tissues, including the nervous system, which suggests that oestrogen’s effects are not limited to primary and secondary sex organs. Increasing evidence supports the role of oestrogen as a neuroprotective compound that can act dependently or independently of ER activation; oestrogen has recently been shown to exhibit intrinsic antioxidant activity that is ER independent. Thus, oestrogen might represent a potential ‘chemical shield’ for neurones. In this article, some recent advances in the elucidation of oestrogen’s beneficial activities on nerve cell survival are discussed.

Section snippets

Direct modulation of neuronal gene transcription by oestrogens

In the mammalian brain, activation of oestrogen receptors (ERs) has long-term genomic effects such as regulation of nerve cell development and protection of the brain during aging², which helps to preserve memory and other cognitive functions that are assigned mainly to the hippocampus. Interestingly, the actions of oestrogens lead to sex differences in the severity of brain damage resulting from transient ischaemia, and in the response of the brain to lesions and chronic stress². The genomic

Interaction of oestrogen with neuronal membranes

Not all of the neuromodulatory activities of oestrogens are a result of nuclear receptor occupation, receptor activation and alteration of gene transcription². For example, in addition to the classical ERs, possible membrane-binding sites (membrane receptors) for various steroids, including oestrogens, are being studied intensively¹⁶. Recently, in vitro data indicate that both membrane and nuclear ERs can be derived from a single transcript¹³. Indeed, oestrogens can also affect neurones via

Oestrogens and neurodegenerative disorders

Depletion of oestrogen in the female rat has been associated with changes in neuronal plasticity and, in general, oestrogens appear to have beneficial effects on mental performance². The decrease in oestrogen levels after the menopause is associated with increased frequency of AD; replacement with oestrogen reduces the risk of women developing AD (28, 29). As a consequence of the oestrogen decline after the menopause, the age-related increased incidence in neurodegenerative disorders and the

Concluding remarks

The steroid hormone oestrogen is now recognized to possess many actions. Oestrogen is sexually dimorphic; it is not restricted to the female as the male sex hormone testosterone [and other steroids that contain a 19-carbon atom structure (C-19 steroids)] can be converted locally to oestradiol in various tissues, including the brain, by an aromatase cytochrome P450 enzyme. The ovaries remain the main source of oestrogen; however, the existence of multiple sites of activity, including the brain,

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Prometaphase arrest-dependent phosphorylation of Bcl-2 family proteins and activation of mitochondrial apoptotic pathway are associated with 17α-estradiol-induced apoptosis in human Jurkat T cells
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The biological activity of estrogens is mediated by three different mechanisms: the intracellular estrogen receptor (ER)-mediated genomic mechanism; the plasma membrane ER-mediated nongenomic mechanism associated with cell signaling pathways; and an ER-independent mechanism [1,2].
In Jurkat T cell clone (JT/Neo), G₂/M arrest, apoptotic sub-G₁ peak, mitochondrial membrane potential (Δψm) loss, and TUNEL-positive DNA fragmentation were induced following exposure to 17α-estradiol (17α-E₂), whereas none of these events (except for G₂/M arrest) were induced in Jurkat cells overexpressing Bcl-2 (JT/Bcl-2). Under these conditions, phosphorylation at Thr161 and dephosphorylation at Tyr15 of Cdk1, upregulation of cyclin B1 level, histone H1 phosphorylation, Cdc25C phosphorylation at Thr-48, Bcl-2 phosphorylation at Thr-56 and Ser-70, Mcl-1 phosphorylation, and Bim phosphorylation were detected in the presence of Bcl-2 overexpression. However, the 17α-E₂-induced upregulation of Bak levels, activation of Bak, activation of caspase-3, and PARP degradation were abrogated by Bcl-2 overexpression. In the presence of the G₁/S blocking agent hydroxyurea, 17α-E₂ failed to induce G₂/M arrest and all apoptotic events including Cdk1 activation and phosphorylation of Bcl-2, Mcl-1 and Bim. The 17α-E₂-induced phosphorylation of Bcl-2 family proteins and mitochondrial apoptotic events were suppressed by a Cdk1 inhibitor but not by aurora A and aurora B kinase inhibitors. Immunofluorescence microscopic analysis showed that an aberrant bipolar microtubule array, incomplete chromosome congression at the metaphase plate, and prometaphase arrest, which was reversible, were the underlying factors for 17α-E₂-induced mitotic arrest. The in vitro microtubule polymerization assay showed that 17α-E₂ could directly inhibit microtubule formation. These results show that the apoptogenic activity of 17α-E₂ was due to the impaired mitotic spindle assembly causing prometaphase arrest and prolonged Cdk1 activation, the phosphorylation of Bcl-2, Mcl-1 and Bim, and the activation of Bak and mitochondria-dependent caspase cascade.
Estrogen synthesis and signaling pathways during aging: From periphery to brain
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Estrogens are the primary female sex hormones and play important roles in both reproductive and non-reproductive systems. Estrogens can be synthesized in non-reproductive tissues such as liver, heart, muscle, bone and brain, and tissue-specific estrogen synthesis is consistent with a diversity of estrogen actions. In this article we review tissue and cell-specific estrogen synthesis and estrogen receptor signaling in three parts: (i) synthesis and metabolism, (ii) the distribution of estrogen receptors and signaling, and (iii) estrogen functions and related disorders, including cardiovascular diseases, osteoporosis, Alzheimer's disease (AD), and Parkinson disease (PD). This comprehensive review provides new insights into estrogens by giving a better understanding of the tissue-specific estrogen effects and their roles in various diseases.
Role of protein phosphatases and mitochondria in the neuroprotective effects of estrogens
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Citation Excerpt :
The antioxidant activity of estrogens observed at high (non-physiological) concentrations (10−5 M) is dependent upon the presence of a phenolic A ring in the steroid structure and is independent of activation of the ERs [10–12,36,110]. A large body of evidence has demonstrated that estradiol possesses antioxidant properties and suppresses oxidative stress in neurons and neuronal cell lines induced by hydrogen peroxide, superoxide anions and other pro-oxidants [8–12,18,23,151]. Both 17α- and 17β-estradiol have similar antioxidant effects [11,12,18,61], suggesting that the neuroprotective effects of estrogens are in part ER-independent.
In the present treatise, we provide evidence that the neuroprotective and mito-protective effects of estrogens are inexorably linked and involve the ability of estrogens to maintain mitochondrial function during neurotoxic stress. This is achieved by the induction of nuclear and mitochondrial gene expression, the maintenance of protein phosphatases levels in a manner that likely involves modulation of the phosphorylation state of signaling kinases and mitochondrial pro- and anti-apoptotic proteins, and the potent redox/antioxidant activity of estrogens. These estrogen actions are mediated through a combination of estrogens receptor (ER)-mediated effects on nuclear and mitochondrial transcription of protein vital to mitochondrial function, ER-mediated, non-genomic signaling and non-ER-mediated effects of estrogens on signaling and oxidative stress. Collectively, these multifaceted, coordinated action of estrogens leads to their potency in protecting neurons from a wide variety of acute insults as well as chronic neurodegenerative processes.
Estradiol and neurodegenerative oxidative stress
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17β-Estradiol (referred to as estradiol in the rest of the text) treatment can protect against a wide range of toxic insults including free radical generators [12,21,60] excitotoxicity [21,136,138], β amyloid-induced toxicity [21] and ischemia [45,59].
Estradiol is a potent preventative against neurodegenerative disease, in part, by activating antioxidant defense systems scavenging reactive oxygen species, limiting mitochondrial protein damage, improving electron transport chain activity and reducing mitochondrial DNA damage. Estradiol also increases the activity of complex IV of the electron transport chain, improving mitochondrial respiration and ATP production under normal and stressful conditions. However, the high oxidative cellular environment present during neurodegeneration makes estradiol a poor agent for treatment of existing disease. Oxidative stress stimulates the production of the hydroperoxide-dependent hydroxylation of estradiol to the catecholestrogen metabolites, which can undergo reactive oxygen species producing redox cycling, setting up a self-generating toxic cascade offsetting any antioxidant/antiapoptotic effects generated by the parent estradiol. Additional disease-induced factors can further perpetuate this cycle. For example dysregulation of the catecholamine system could alter catechol-O-methyltransferase-catalyzed methylation, preventing removal of redox cycling catecholestrogens from the system enhancing pro-oxidant effects of estradiol.
17α-Estradiol arrests cell cycle progression at G<inf>2</inf>/M and induces apoptotic cell death in human acute leukemia Jurkat T cells
2008, Toxicology and Applied Pharmacology
A pharmacological dose (2.5–10 μM) of 17α-estradiol (17α-E₂) exerted a cytotoxic effect on human leukemias Jurkat T and U937 cells, which was not suppressed by the estrogen receptor (ER) antagonist ICI 182,780. Along with cytotoxicity in Jurkat T cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, PARP degradation, and DNA fragmentation were induced. The cytotoxicity of 17α-E₂ was not blocked by the anti-Fas neutralizing antibody ZB-4. While undergoing apoptosis, there was a remarkable accumulation of G₂/M cells with the upregulatoin of cdc2 kinase activity, which was reflected in the Thr56 phosphorylation of Bcl-2. Dephosphorylation at Tyr15 and phosphorylation at Thr161 of cdc2, and significant increase in the cyclin B1 level were underlying factors for the cdc2 kinase activation. Whereas the 17α-E₂-induced apoptosis was completely abrogated by overexpression of Bcl-2 or by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G₂/M cells significantly increased. The caspase-8 inhibitor z-IETD-fmk failed to influence 17α-E₂-mediated caspase-9 activation, but it markedly reduced caspase-3 activation and PARP degradation with the suppression of apoptosis, indicating the contribution of caspase-8; not as an upstream event of the mitochondrial cytochrome c release, but to caspase-3 activation. In the presence of hydroxyurea, which blocked the cell cycle progression at the G₁/S boundary, 17α-E₂ failed to induce the G₂/M arrest as well as apoptosis. These results demonstrate that the cytotoxicity of 17α-E₂ toward Jurkat T cells is attributable to apoptosis mainly induced in G₂/M-arrested cells, in an ER-independent manner, via a mitochondria-dependent caspase pathway regulated by Bcl-2.

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Trends in Pharmacological Sciences

ViewpointThe female sex hormone oestrogen as a neuroprotectant

Abstract

Section snippets

Direct modulation of neuronal gene transcription by oestrogens

Interaction of oestrogen with neuronal membranes

Oestrogens and neurodegenerative disorders

Concluding remarks

Brain Res. Bull.

Steroids

Front. Neuroendocrinol.

Trends Neurosci.

Trends Neurosci.

Biochem. Biophys. Res. Commun.

Lancet

Trends Neurosci.

Progr. Neurobiol.

Biochem. J.

Endocr. Rev.

Dev. Neurosci.

J. Comp. Neurol.

Trends Endocrinol. Metab.

J. Neurosci.

Mol. Cell. Biol.

Nucleic Acids Res.

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

J. Neurosci.

Viewpoint
The female sex hormone oestrogen as a neuroprotectant