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Neurosteroids as regenerative agents in the brain: therapeutic implications

Nature Reviews Endocrinology volume 9, pages 241–250 (2013)Cite this article

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Abstract

Regenerative therapeutics hold the promise of self-renewal and repair. Ageing and age-associated neurodegenerative diseases are marked by a decline in self-renewal and repair, but a capacity for regeneration is retained. The challenge faced by researchers developing molecular therapeutics to promote self-renewal in the nervous system is to activate regenerative and repair pathways often in the context of progressive degeneration. Neurosteroids regulate both regeneration and repair systems in the brain, and among this class of molecules, allopregnanolone has been broadly investigated for its role to promote regeneration in both the central and peripheral nervous systems. In the brain, allopregnanolone induced generation and survival of new neurons in the hippocampus of both aged mice and mice with Alzheimer disease, accompanied by restoration of associative learning and memory function. In the brain of mice with Alzheimer disease, allopregnanolone increased liver X receptor and pregnane X receptor expression, reduced amyloid-β and microglial activation, and increased markers of myelin and white matter generation. Therapeutic windows for efficacy of allopregnanolone were evident in the brains of mice with both normal ageing and Alzheimer disease. Allopregnanolone dose and a regenerative treatment regimen of intermittent allopregnanolone exposure were determining factors regulating therapeutic efficacy. Allopregnanolone serves as proof of concept for therapeutics that target endogenous regeneration, windows of therapeutic opportunity for regeneration, and critical system biology factors that will determine the efficacy of regeneration.

Key Points

  • The neurosteroid allopregnanolone promotes regeneration in the brain, recovery of learning and memory function, and reduces Alzheimer disease pathology in preclinical studies of efficacy

  • Therapeutic windows of allopregnanolone preclinical efficacy are defined by age and Alzheimer disease burden

  • Allopregnanolone administered intermittently to synergize with temporal cycles of endogenous regeneration promoted renewal and repair, whereas continuous infusions of allopregnanolone were antiregenerative in mouse models of Alzheimer disease

  • Allopregnanolone is poised to become the first endogenous regenerative therapeutic to be clinically developed for the prevention, delay or treatment of Alzheimer disease

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Figure 1: Mechanism of allopregnanolone-induced neural stem cell and oligodendrocyte precursor progenitor mitosis.
Figure 2: Paradigm of allopregnanolone treatment, behavioural assessments and survival of newly generated neurons in wild-type mice and in the 3×TgAD mice across the life course.
Figure 3: Targeting regeneration and disease mechanisms promotes therapeutic efficacy.
Figure 4: Optimization of allopregnanolone treatment regimens for regeneration and repair.
Figure 5: Theoretical window of opportunity for therapeutic efficacy to promote endogenous regeneration of neural stem cells versus stem-cell-based therapies.

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Acknowledgements

The work that led to this Review was supported by grants from the NIH National Institute on Aging (U01 AG031115), the Alzheimer Drug Development Foundation, the Kenneth T. and Eileen L. Norris Foundation, and The California Institute for Regenerative Medicine (DR2-05410) to R. D. Brinton and by the SC CTSI NIH National Center for Advancing Translational Science (UL1 RR031986). The invaluable contributions of J. Wang, S. Chen and R. Irwin of the University of Southern California to our discovery and translational research endeavours described herein are gratefully acknowledged.

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  1. Department of Pharmacology and Pharmaceutical Sciences, Department of Neurology, School of Pharmacy, Keck School of Medicine, University of Southern California, Los Angeles, 90033, CA, USA

    Roberta D. Brinton

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The author declares that she has filed applications for patents on therapeutic regimen and method of use of allopregnanolone for neurodegenerative diseases.

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Brinton, R. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat Rev Endocrinol 9, 241–250 (2013). https://doi.org/10.1038/nrendo.2013.31

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