The Estrogen Receptor Is Not Essential for All Estrogen Neuroprotection: New Evidence from a New Analog

doi:10.1006/nbdi.2002.0478

Neurobiology of Disease

Volume 9, Issue 3, April 2002, Pages 282-293

https://doi.org/10.1006/nbdi.2002.0478 Get rights and content

Abstract

We synthesized an estrogen analog, ZYC-5, lacking activity at the classical estrogen receptor and examined its neuroprotective potential against necrosis induced by N-methyl-d-aspartate (NMDA) and apoptosis/necrosis induced by the NMDA receptor antagonist (+)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). ZYC-5 protected cortical neurons in a dose-dependent manner, and the neuroprotection was more robust than with 17β-estradiol. The effect of ZYC-5 was not mediated by the classical estrogen receptor, because it was unaffected by the antagonists 4-hydroxytamoxifen and ICI 182,780. The ZYC-5 protection against excitotoxicity was not directly mediated through the NMDA receptor, because there was no effect of ZYC-5 on NMDA current or the intracellular calcium increase induced by NMDA. Results obtained with the free-radical-sensitive dye, dihydroethidium, suggested that the neuroprotection of ZYC-5 was partly related to its radical scavenging properties. Although some of estrogen's neuroprotective effects may depend upon the estrogen receptor, our results suggest the possibility of neuroprotection without hormonal side effects.

References (54)

C. Behl et al.
The female sex hormone oestrogen as a neuroprotectant
Trends Pharmacol. Sci.
(1999)
C. Behl et al.
17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro
Biochem. Biophys. Res. Commun.
(1995)
S.C. Bondy et al.
The relationship between excitotoxicity and oxidative stress in the central nervous system
Free Radi. Biol. Med.
(1993)
L.M. Garcia-Segura et al.
Neuroprotection by estradiol
Prog. Neurobiol.
(2001)
P.S. Green et al.
Phenolic A ring requirement for the neuroprotective effects of steroids
J. Steroid Biochem. Mol. Biol.
(1997)
P.S. Green et al.
Neuroprotective effects of estrogens: Potential mechanisms of action
Int. J. Dev. Neurosci.
(2000)
G. Grynkiewicz et al.
A new generation of Ca2+ indicators with greatly improved fluorescence properties
J. Biol. Chem.
(1985)
B.J. Gwag et al.
Slowly triggered excitotoxicity occurs by necrosis in cortical cultures
Neuroscience
(1997)
V.W. Henderson
Estrogen, cognition, and a woman's risk of Alzheimer's disease
Am. J. Med.
(1997)
J.Y. Hwang et al.
N-Methyl-d-aspartate receptor blockade induces neuronal apoptosis in cortical culture
Exp. Neurol.
(1999)

W.H. Lunn et al.

The adamantyl carbonium ion as a dehydrogenating agent, its reactions with estrone

Tetrahedron

(1968)

J.W. McDonald et al.

Susceptibility to apoptosis is enhanced in immature cortical neurons

Brain Res.

(1997)

C.P. Miller et al.

In vitro antioxidant effects of estrogens with a hindered 3-OH function on the copper-induced oxidation of low density lipoprotein

Steroids

(1996)

A.D. Mooradian

Antioxidant properties of steroids

J. Steroid Biochem. Mol. Biol.

(1993)

R.F. Regan et al.

Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures

Brain Res.

(1997)

V.A. Rifici et al.

The inhibition of low-density lipoprotein oxidation by 17-beta estradiol

Metabolism

(1992)

P.J. Shughrue et al.

Estrogen is more than just a “sex hormone”: Novel sites for estrogen action in the hippocampus and cerebral cortex

Front. Neuroendocrinol.

(2000)

C.A. Singer et al.

Estrogen protects primary cortical neurons from glutamate toxicity

Neurosci. Lett.

(1996)

M.X. Tang et al.

Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease

Lancet

(1996)

F. Terro et al.

N-methyl-d-aspartate receptor blockade enhances neuronal apoptosis induced by serum deprivation

Neurosci. Lett.

(2000)

C.E. Weaver et al.

17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors

Brain Res.

(1997)

Y.H. Bae et al.

Anti-oxidative neuroprotection by estrogens in mouse cortical cultures

J. Korean Med. Sci.

(2000)

C. Behl et al.

Neuroprotection against oxidative stress by estrogens: Structure–activity relationship

Mol. Pharmacol.

(1997)

S. Benson

Hormone replacement therapy and Alzheimer's disease: An update on the issues

Health Care Women Int.

(1999)

C. Beyer

Estrogen and the developing mammalian brain

Anat. Embryol. (Berlin)

(1999)

S.J. Birge

The role of estrogen in the treatment of Alzheimer's disease

Neurology

(1997)

Cited by (40)

Targeting RORs nuclear receptors by novel synthetic steroidal inverse agonists for autoimmune disorders
2018, Bioorganic and Medicinal Chemistry
Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORγt activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORγt activity at low micromolar concentrations.
Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms
2017, Frontiers in Neuroendocrinology
Schizophrenia is a complex neuropsychiatric illness with marked sex differences. Women have later onset and lesser symptoms, which has led to the hypothesis that estrogens are protective in schizophrenia. Cognitive dysfunction is a hallmark of the disease and the symptom most correlated with functional outcome. Here we describe a number of mechanisms by which estrogens may be therapeutic in schizophrenia, with a focus on cognitive symptoms. We review the relationship between estrogens and brain derived neurotrophic factor, neuroinflammation, NMDA receptors, GABA receptors, and luteinizing hormone. Exploring these pathways may enable novel treatments for schizophrenia and a greater understanding of this devastating disease.
Ketamine
2013, Novel Psychoactive Substances: Classification, Pharmacology and Toxicology
Ketamine was introduced as an anaesthetic in the 1960s and continues to be used therapeutically both as an anaesthetic and also increasingly in pain management. In addition to use in humans, ketamine is widely used as an anaesthetic in veterinary medicine. It is used in research as a pharmacological model of schizophrenia. In recent years, ketamine has increasingly been used as a recreational drug. Though it is now a controlled substance in many countries in the world due to its psychotropic properties, its use as a recreational drug has become a worldwide phenomenon. In addition to the risk of acute toxicity associated with ketamine use, long-term ketamine toxicity can produce significant adverse effects and consequently lead to a burden on healthcare resources. In this chapter, we summarize the pathological changes in the different organs of animal models and humans, including its toxicity on central nervous system (CNS), urogenital system, intestine, pancreas, adrenal gland, liver, heart and immune system. The effects on the combination of ketamine and alcohol were also addressed in a number of the models of chronic ketamine toxicity. This is followed by a summary of the human data on patterns of acute and chronic toxicity reported from recreational and dependent use of ketamine.
The many faces of the adamantyl group in drug design
2011, European Journal of Medicinal Chemistry
Citation Excerpt :
The extent of cell death was unchanged when the cells were pre-incubated with up to 10 μM 17β-estradiol; however, pre-incubation of the cells with 9 for 12 and 24 h was shown to attenuate cell death in a dose-dependent fashion, with survival close to control levels at 1 μM [28]. The ED50 value of 9 at cloned human estrogen receptors was 100-times greater than the ED50 value of 17β-estradiol (1 nM) [28], which indicates that in 9, the well-established neuroprotective effects of the estrogen group have been decoupled from the estrogen receptor mediated properties [28,29]. The extended pre-incubation times that were required to observe the neuroprotective effects of 9 (12, 24 h) were ascribed to 9 processing membrane-associated radicals in intracellular compartments, which concurs with the higher clogP value of 9, relative 17β-estradiol, which would be more soluble in the cytosol.
Adamantyl-based compounds are used clinically for the treatment of neurological conditions, as anti-viral agents and as agents against type 2 diabetes. The value of the adamantyl group in drug design is multidimensional. The hydrophobic substituent constant for the adamantyl group has been estimated from the calculated partition coefficients (clogP values) of 31 adamantyl-bearing compounds in the clinic or in development as π_adamantyl = 3.1, which indicates that the logP value of a compound with high water solubility (logP < < 0) could be moved with an adamantyl-based modification to a region that is more clinically useful. The steric bulk of the adamantyl group can: (i) restrict or modulate intramolecular reactivity; and (ii) impede the access of hydrolytic enzymes, thereby increasing drug stability and plasma half life. The value of the adamantyl group in drug design has been recognized most recently in the design of agents to treat iron overload disease (in development), malaria (in clinical trials) and type 2 diabetes (in the clinic).
Divergent mechanisms for trophic actions of estrogens in the brain and peripheral tissues
2011, Brain Research
17β-estradiol (E₂) can enhance reproductive, cognitive, and affective functions; however, the mechanisms by which E₂ has these effects need to be better understood. Pleiotrophic effects of E₂ can occur via traditional and novel actions at various forms of estrogen receptors (ERs). In the central nervous system, trophic effects of E₂ may be related to beneficial effects of hormone replacement therapy (HRT). However, in peripheral reproductive tissues, E₂'s capacity to evoke growth can increase risk of cancers. This review focuses on investigations aimed at elucidating divergent mechanisms of steroids to promote trophic effects in the brain, independent of effects on peripheral reproductive tissues. First, actions of estrogens via ERα or ERβ for peripheral growth (carcinogen-induced tumors, uterine growth) and hippocampus-dependent behaviors (affect, cognition) are described. Second, factors that influence these effects of estrogens are described (e.g. experience, timing/critical windows, non-ER mechanisms). Third, effects of estrogens at ERβ related to actions of progestogens, such as 5α-pregnan-3α-ol-20-one (3α,5α-THP) are described. In summary, effects of E₂ may occur via multiple mechanisms, which may underlie favorable effects in the brain with minimal peripheral trophic effects.
Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?
2009, Neuropharmacology
An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a pro-oxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PV-interneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, although essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redox balance leading to schizophrenia symptoms in late adolescence and early adulthood.

View all citing articles on Scopus

¹: To whom correspondence and reprint requests should be addressed. Fax: (314) 454-2523. E-mail: [email protected].

View full text

Regular ArticleThe Estrogen Receptor Is Not Essential for All Estrogen Neuroprotection: New Evidence from a New Analog

Abstract

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

Free Radi. Biol. Med.

Prog. Neurobiol.

J. Steroid Biochem. Mol. Biol.

Int. J. Dev. Neurosci.

J. Biol. Chem.

Neuroscience

Am. J. Med.

Exp. Neurol.

Tetrahedron

Brain Res.

Steroids

J. Steroid Biochem. Mol. Biol.

Brain Res.

Metabolism

Front. Neuroendocrinol.

Neurosci. Lett.

Lancet

Neurosci. Lett.

Brain Res.

Anti-oxidative neuroprotection by estrogens in mouse cortical cultures

J. Korean Med. Sci.

Neuroprotection against oxidative stress by estrogens: Structure–activity relationship

Mol. Pharmacol.

Hormone replacement therapy and Alzheimer's disease: An update on the issues

Health Care Women Int.

Estrogen and the developing mammalian brain

Anat. Embryol. (Berlin)

The role of estrogen in the treatment of Alzheimer's disease

Neurology

Regular Article
The Estrogen Receptor Is Not Essential for All Estrogen Neuroprotection: New Evidence from a New Analog