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Development of 17  -Estradiol as a Neuroprotective Therapeutic Agent: Rationale and Results from a Phase I Clinical Study
MIGENIX Corporation, San Diego, California 92130, USA
Address for correspondence: James A. Dykens, MIGENIX Corporation, 12780 High Bluff Dr., San Diego, CA 92130. Voice: 858-509-5617; fax: 858-793-7805. jdykens{at}migenix.com
17
 -estradiol (17-E2) differs from its isomer, the potent feminizing hormone 17ß-estradiol (17ß-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, 17-E2 is as potent as 17ß-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 17-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, 17-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 17-E2 (sodium sulfate conjugate) are presented here, and several options for its future clinical assessment are discussed.
Key Words: Alzheimer's disease • Parkinson's disease • amyotrophic lateral sclerosis • Friedreich's ataxia • mitochondria • apoptosis • lipid peroxidation This article has been cited by other articles:
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