Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione

doi:10.1016/S0306-4522(97)00595-2

Neuroscience

Volume 84, Issue 1, 3 February 1998, Pages 7-10

https://doi.org/10.1016/S0306-4522(97)00595-2 Get rights and content

Abstract

Post-menopausal estrogen replacement therapy is associated with a reduction in the risk of Alzheimer's disease and has been reported to improve cognitive functioning in several small clinical trials. The present study evaluates the dependence of estrogenic neuroprotection on the presence of estrogen receptors using the murine neuronal cell line, HT-22, exposed to the neurotoxic β-amyloid peptide. These cells lack functional estrogen receptors. The amyloid peptide killed 50–60% of these cells and concurrent treatment with either of three estratrienes, β-estradiol, α-estradiol, or estratrien-3-ol, resulted in a dose-dependent protection. The potency of this estrogen neuroprotection was dependent on the presence of glutathione in the culture media. The presence of reduced glutathione in the media increases the neuroprotective potency of estrogens by an average of 400-fold. These results demonstrate that a nuclear estrogen receptor is not necessary for the neuroprotective actions of estrogens; however, the presence of an appropriate antioxidant in the extracellular milieu is needed for estratriene neuroprotection at physiologically and pharmacologically relevant doses. These data suggest the possibility of combined estrogen-antioxidant therapy for neurodegenerative diseases such as Alzheimer's disease.

Section snippets

Unlinked refs

[11]

Acknowledgements

The authors wish to thank Dr David Schubert for his generous gift of the HT-22 cells. This work was supported by Apollo Biopharmaceutics, Inc. and NIA grant P01 AG10485 and PSG is supported on NIH grant T32 AG00196.

References (29)

C Behl et al.
17β-estradiol protects neurons from oxidative stress-induced cell death in vitro
Biochem. biophys. Res. Commun.
(1995)
G Benzi et al.
Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system
Free Rad. Biol. Med.
(1995)
J Bishop et al.
Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro
Molec. cell. Neurosci.
(1994)
P.S Green et al.
Estradiol protects against β-amyloid (25–35)-induced toxicity in SK-N-SH cells
Neurosci. Lett.
(1996)
J Nakao et al.
Estradiol-binding sites in rat aortic smooth muscle cells in culture
Atherosclerosis
(1981)
O Rabbani et al.
17β-estradiol attenuates fimbra lesion-induced decline of ChAT-immunoreactive neurons in the rat medial septum
Expl Neurol.
(1997)
C.A Singer et al.
Estrogen protects primary cortical neurons from glutamate toxicity
Neurosci. Lett.
(1996)
K Sugioka et al.
Estrogens as natural antioxidants of membrane phospholipid peroxidation
Fedn Eur. biochem. Socs Lett.
(1987)
M.X Tang et al.
Effect of oestrogen during menopause on risk an age of onset of Alzheimer's disease
Lancet
(1996)
B.S Winkler et al.
The redox couple between glutathione and ascorbic acid: a chemical and physiological perspective
Free Rad. Biol. Med.
(1994)

M Wong et al.

Electrophysiological evidence for a rapid membrane action of gonadal steroids, 17β-estradiol, on CA1 pyramidal neurons of the rat hippocampus

Brain Res.

(1991)

F Baronti et al.

Deprenyl effects on levodopa pharmacodynamics, mood, and free radical scavenging

Neurology

(1992)

C Behl et al.

Neuroprotection against oxidative stress by estrogens: structure–activity relationship

Molec. Pharmac.

(1997)

Y Goodman et al.

Estrogen attenuates and corticosterone exacerbates excitoxicity, oxidative injury, and amyloid β-peptide toxicity in hippocampal neurons

J. Neurochem.

(1996)

Cited by (172)

Unveiling OSCP as the potential therapeutic target for mitochondrial dysfunction-related diseases
2024, Life Sciences
Mitochondria are important organelles in cells responsible for energy production and regulation. Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases. Oligomycin sensitivity-conferring protein (OSCP), a component of the inner mitochondrial membrane, has been studied for a long time. OSCP is a component of the F1Fo-ATP synthase in mitochondria and is closely related to the regulation of the mitochondrial permeability transition pore (mPTP). Studies have shown that OSCP plays an important role in cardiovascular disease, neurological disorders, and tumor development. This review summarizes the localization, structure, function, and regulatory mechanisms of OSCP and outlines its role in cardiovascular disease, neurological disease, and tumor development. In addition, this article reviews the research on the interaction between OSCP and mPTP. Finally, the article suggests future research directions, including further exploration of the mechanism of action of OSCP, the interaction between OSCP and other proteins and signaling pathways, and the development of new treatment strategies for mitochondrial dysfunction. In conclusion, in-depth research on OSCP will help to elucidate its importance in cell function and disease and provide new ideas for the treatment and prevention of related diseases.
The sex-specific interaction of the microbiome in neurodegenerative diseases
2019, Brain Research
Several neurologic diseases exhibit different prevalence and severity in males and females, highlighting the importance of understanding the influence of biologic sex and gender. Beyond host-intrinsic differences in neurologic development and homeostasis, evidence is now emerging that the microbiota is an important environmental factor that may account for differences between men and women in neurologic disease. The gut microbiota is composed of trillions of bacteria, archaea, viruses, and fungi, that can confer benefits to the host or promote disease. There is bidirectional communication between the intestinal microbiota and the brain that is mediated via immunologic, endocrine, and neural signaling pathways. While there is substantial interindividual variation within the microbiota, differences between males and females can be detected. In animal models, sex-specific microbiota differences can affect susceptibility to chronic diseases. In this review, we discuss the ways in which neurologic diseases may be regulated by the microbiota in a sex-specific manner.
Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury
2017, Progress in Neurobiology
Citation Excerpt :
The observation that estrogens are potent in preventing ROS production led us to investigate their role in inhibition of lipid peroxidation. In neuroprotection assays in vitro, we showed that estrogens interact with the abundant aqueous soluble anti-oxidant, glutathione (Green et al., 1998; Gridley et al., 1998). Also since estrogens have a log P of about 3, they reside in the membrane component of cells (Liang et al., 2001), where they could prevent oxidation of phospholipids.
There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging and brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations in the context of aging, cognition, stroke, and traumatic brain injury. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.
High and low concentration of 17α-estradiol protect cerebellar granule neurons in different time windows
2017, Biochemical and Biophysical Research Communications
Citation Excerpt :
Pretreatment with 10 μM did not affect the synthesis of the glutamate cysteine ligase catalytic subunit GCLC of the rate limiting enzyme GCL in GSH synthesis (data not shown), suggesting that reduced activity of the enzyme and/or depletion of GSH are responsible for the reduced GSH levels [23]. A sufficient level of the key antioxidant GSH is needed for neuroprotective actions of 17β-estradiol and 17α-estradiol in nM and μM doses [24]. Thus, the neurons are likely to be more vulnerable for an excitotoxic stimulus if GSH levels are decreased at the time point for administration because of reduced capacity to scavenge excess ROS production, and this probably caused the glutamate-induced increase in ROS levels after 1 h with pretreatment 10 μM 17α-estradiol.
17α-estradiol is a hormonally inactive isomer of 17β-estradiol, but with similar potency as neuroprotector. However, we have previously reported that pretreatment with high concentration (10 μM) of both estrogens abolishes their neuroprotection in rat cerebellar granule neurons. Here, we have examined neuroprotective properties of 17α-estradiol against glutamate-induced excitotoxicity in chicken cerebellar granule neurons using low (1 nM) and high concentration.17α-Estradiol, 1 nM, was neuroprotective when glutamate was administered after a pretreatment period of 24 h, but not when coadministered with glutamate. In contrast, 10 μM was protective when coadministered with glutamate, but was not efficient when glutamate was administered after a pretreatment period. The difference in protection was linked to a stronger calcium response during glutamate exposure in the non-protective treatments. In addition, the pretreatment period with 10 μM was accompanied by increased protein level of the N-methyl-d-aspartate receptor subunit NR2B and reduced glutathione level. Thus, 17α-estradiol has a concentration and time dependent protective effect against glutamate-induced cell death.
A novel mechanism of non-feminizing estrogens in neuroprotection
2017, Experimental Gerontology
Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in an in vitro assay using a panel of > 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large bulky group at the C2 or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C or D rings either reduced or did not markedly change neuroprotection. Collectively, there was a negative correlation between binding to ERs and neuroprotection with the more potent compounds showing no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. We demonstrated that these non-feminizing estrogens engage in a redox cycle with glutathione, using the hexose monophosphate shunt to apply cytosolic reducing potential to cellular membranes. Together, these results demonstrate that non-feminizing estrogens are neuroprotective and protect brain from the induction of ischemic- and Alzheimer's disease (AD)-like neuropathology in an animal model. These features of non-feminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, as they are not expected to show the side effects of chronic estrogen therapy that are mediated by ER actions in the liver, uterus and breast.
17β-Estradiol/N-acetylcysteine interaction enhances the neuroprotective effect on dopaminergic neurons in the weaver model of dopamine deficiency
2016, Neuroscience
The weaver mouse, is a phenocopy of Parkinson’s disease (PD) in which dopaminergic neurons degenerate gradually during development, reaching at P21 a neurodegeneration of 55%. Thus, the weaver mouse constitutes an appropriate in vivo PD model for investigating the effect of neuroprotective agents. In the present study, long-term treatment (from P1 to P21) with 17β-estradiol (17β-estradiol) significantly protected the dopaminergic neurons in the substantia nigra (SN) of weaver mouse by 54%, as was detected by immunohistochemical experiments, using the specific antibody against tyrosine hydroxylase (TH). This dopaminergic neuroprotection is in line with our biochemical results showing that 17β-estradiol treatment significantly decreased the high lipid peroxidation levels seen in the SN of weaver mouse, indicating high oxidative stress. Interestingly, co-administration of 17β-estradiol with N-acetylcysteine (NAC, precursor molecule of glutathione (GSH)) further significantly increased the survival of dopaminergic neurons in the SN (by 85%), with a parallel further decrease of lipid peroxidation to normal levels. Our results show the in vivo neuroprotective effect of 17β-estradiol, which is strongly enhanced by co administration of NAC, indicating a strong synergistic effect of the two drugs. Furthermore, the main mechanism underlying this neuroprotective action seems to be the reversal of the oxidative stress shown by the high peroxidation levels. These results could be of clinical relevance since both drugs are already used separately in the clinic, 17β-estradiol for treatment of PD and NAC as a mucolytic agent and for the treatment of several disorders.

View all citing articles on Scopus

View full text

Letter to NeuroscienceNuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione

Abstract

Section snippets

Unlinked refs

Acknowledgements

Biochem. biophys. Res. Commun.

Free Rad. Biol. Med.

Molec. cell. Neurosci.

Neurosci. Lett.

Atherosclerosis

Expl Neurol.