Neurosteroids as regenerative agents in the brain: Therapeutic implications

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. .
Nature Reviews Endocrinology (Impact Factor: 13.28). 02/2013; 9(4). DOI: 10.1038/nrendo.2013.31
Source: PubMed


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.

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    • "Examples of small multifunctional molecules with interesting perspectives for the treatment of lesions of the nervous system are steroids, such as progesterone and its synthetic analogs [2] [5] [6] [56] "
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    ABSTRACT: Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid has major assets: it easily crosses the blood-brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of TBI biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials.
    Full-text · Article · Nov 2015 · The Journal of steroid biochemistry and molecular biology
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    • "Examples of small multifunctional molecules with interesting perspectives for the treatment of lesions of the nervous system are steroids, such as progesterone and its synthetic analogs [2] [5] [6] [56] "
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    ABSTRACT: Levels of steroids in the adult central nervous system (CNS) show marked changes in response to stress, degenerative disorders and injury. However, their analysis in complex matrices such as fatty brain and spinal cord tissues, and even in plasma, requires accurate and precise analytical methods. Radioimmunoassays (RIA) and enzyme-linked immunosorbent assays, even with prepurification steps, do not provide sufficient specificity, and they are at the origin of many inconsistent results in the literature. The analysis of steroids by mass spectrometric methods has become the gold standard for accurate and sensitive steroid analysis. However, these technologies involve multiple purification steps prone to errors, and they only provide accurate reference values when combined with careful sample workup. In addition, the interpretation of changes in CNS steroid levels is not an easy task because of their multiple sources: the endocrine glands and the local synthesis by neural cells. In the CNS, decreased steroid levels may reflect alterations of their biosynthesis, as observed in the case of chronic stress, post-traumatic stress disorders or depressive episodes. In such cases, return to normalization by administering exogenous hormones or by stimulating their endogenous production may have beneficial effects. On the other hand, increases in CNS steroids in response to acute stress, degenerative processes or injury may be part of endogenous protective or rescue programs, contributing to the resistance of neural cells to stress and insults. The aim of this review is to encourage a more critical reading of the literature reporting steroid measures, and to draw attention to the absolute need for well-validated methods. We discuss reported findings concerning changing steroid levels in the nervous system by insisting on methodological issues. An important message is that even recent mass spectrometric methods have their limits, and they only become reliable tools if combined with careful sample preparation. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Steroids
    • "The recent studies showed that in both animal and human brains neurosteroids levels were modified in pathological conditions (Brinton, 2013). The observed in our study, decreased level of Aro gene expression suggests fewer estrogens production, so the protection against ROS is disturbed and the brain tissue is more prone to neurons injury. "
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    ABSTRACT: The study was designed to examine the effects of silver AgNPs, 20 nm) and titanium dioxide (Aeroxide® P25 TiO2NPs, 21 nm) nanoparticles on brain oxidative stress parameters, its antioxidant potential and brain renin-angiotensin system (RAS) in vivo. The analysis was performed 28 days after single dose injection of TiO2NPs and AgNPs (10 or 5 mg/kg body weight, respectively). The AgNPs, but not TiO2NPs, administration resulted in decreased lipid and cholesterol peroxidation. Antioxidant enzymes gene expression and/or activity were changed differently for TiO2NPs and AgNPs group. The TiO2NPs decreased aromatase gene expression, and glutathione peroxidase and reductase activities. In AgNPs group the sodium dismutase 1 and glutathione reductase mRNA levels were decreased as opposed to their activities. Both NPs altered the expression of brain RAS genes (angiotensinogen, renin, angiotensin I converting enzyme 1 and 2), but only TiO2NPs caused similar changes on protein level. The expression of amyloid beta precursor protein gene was not altered by any kind of injected NPs. The TiO2NPs were more potent modulator of gene expression in the brain than AgNPs, despite the two times lower dosage. These results suggest that AgNPs and TiO2NPs exposure may modulate the brain function, but with different strength. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Aug 2015 · Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association
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