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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00359

Neurosteroid metabolites of gonadal steroid hormones in neuroprotection: implications for sex differences in neurodegenerative disease

  • 1Department of Biomedical Sciences, University of Guelph, Canada

Gonadal steroid hormones are neurotrophic and neuroprotective. These effects are modulated by local metabolism of the hormones within the brain. Such control is necessary to maintain normal function, as several signaling pathways that are activated by gonadal steroid hormones in the brain can also become dysregulated in disease. Metabolites of the gonadal steroid hormones – particularly 3α-hydroxy, 5α-reduced neurosteroids – are synthesized in the brain and can act through different mechanisms from their parent steroids. These metabolites may provide a mechanism for modulating the responses to their precursor hormones, thereby providing a regulatory influence on cellular responses. In addition, there is evidence that the 3α-hydroxy, 5α-reduced neurosteroids are neuroprotective in their own right, and therefore may contribute to the overall protection conferred by their precursors. In this review, the rapidly growing body of evidence supporting a neuroprotective role for this class of neurosteroids will be considered, including a discussion of potential mechanisms that may be involved. In addition, we explore the hypothesis that differences between males and females in local neurosteroid production may contribute to sex differences in the development of neurodegenerative disease.

Keywords: Neurosteroids, sex differences, Alzheimer's disease, Neuroprotection, neurodegenerative disease

Received: 03 Jul 2018; Accepted: 12 Sep 2018.

Edited by:

Jordan Marrocco, Rockefeller University, United States

Reviewed by:

Jamie Maguire, Tufts University School of Medicine, United States
Michael Schumacher, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Richard G. Hunter, University of Massachusetts Boston, United States  

Copyright: © 2018 Mendell and MacLusky. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Neil J. MacLusky, Department of Biomedical Sciences, University of Guelph, Ontario, Canada, nmaclusk@uoguelph.ca