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Cited by 87Neurological Disorders and TreatmentsEstrogen and related hormone effectsAlzheimer's disease research and treatments

Development of 17α‐Estradiol as a Neuroprotective Therapeutic Agent: Rationale and Results from a Phase I Clinical Study

DYKENS, JAMES A., MOOS, WALTER H., HOWELL, NEIL·2005·Annals of the New York Academy of Sciences
DOI 10.1196/annals.1347.008
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Abstract

A bstract: 17α‐estradiol (17α‐E2) differs from its isomer, the potent feminizing hormone 17β‐estradiol (17β‐E2), only in the stereochemistry at one carbon, but this is sufficient to render it at least 200‐fold less active as a transactivating hormone. Despite its meager hormonal activity, 17α‐E2 is as potent as 17β‐E2 in protecting a wide variety of cell types, including primary neurons, from a diverse array of lethal and etiologically relevant stressors, including amyloid toxicity, serum withdrawal, oxidative stress, excitotoxicity, and mitochondrial inhibition, among others. Moreover, both estradiol isomers have shown efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD). Data from many labs have yielded a mechanistic model in which 17α‐E2 intercalates into cell membranes, where it terminates lipid peroxidation chain reactions, thereby preserving membrane integrity, and where it in turn is redox cycled by glutathione or by NADPH through enzymatic coupling. Maintaining membrane integrity is critical to mitochondrial function, where loss of impermeability of the inner membrane initiates both necrotic and apoptotic pathways. Thus, by serving as a mitoprotectant, 17α‐E2 forestalls cell death and could correspondingly provide therapeutic benefit in a host of degenerative diseases, including AD, PD, Friedreich's ataxia, and amyotrophic lateral sclerosis, while at the same time circumventing the common adverse effects elicited by more hormonally active analogues. Positive safety and pharmacokinetic data from a successful phase I clinical study with oral 17α‐E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.

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  • Estradiol has shown neuroprotective efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD).

    “Similarly, estradiol has shown neuroprotective efficacy in animal models of stroke, Alzheimer's disease (AD), and Parkinson's disease (PD)192.”

    From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [192]

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Authors
DYKENS, J. A., MOOS, W. H., & HOWELL, N.
Corresponding author
DYKENS, JAMES A.
ORCID
Venue
Annals of the New York Academy of Sciences
Publisher
Wiley
Published
2005-06
Volume
1052
Issue
1
Pages
116-135
ISSN
  • 0077-8923 (ISSN-L)
  • 1749-6632
DOI
10.1196/annals.1347.008
OpenAlex
W1991853902
Cited by
87
References
94
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 10 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 5
FWCI
3.82
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 231 d)
Locations
  • Annals of the New York Academy of Sciences (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
17α-estradiol, neuroprotection, membrane intercalation, lipid peroxidation, mitoprotection, mitochondrial function, oxidative stress, amyloid toxicity, excitotoxicity, stroke, Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, amyotrophic lateral sclerosis, NADPH, pharmacokinetics, drug safety, neurodegenerative diseases
MeSH terms
Aged, Alzheimer Disease, Animals, Estradiol, Female, Humans, Middle Aged, Mitochondria, Neurons, Parkinson Disease, Receptors, Estrogen, Stereoisomerism, Lipid Peroxidation, Apoptosis, Clinical Trials, Phase I as Topic, Oxidative Stress, Neuroprotective Agents, Neurodegenerative Diseases, Stroke

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