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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    • "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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    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 08/2015; DOI:10.1016/j.fct.2015.08.005 · 2.90 Impact Factor
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    • "Research data consistently suggests that a small molecule, the neurosteroid allopregnanolone (APα) capable of permeating the brain-blood-barrier, is a latent restorative therapeutic agent for reestablishing neuronal circuits in hippocampus and also the nigrostrital tract. Supportive data demonstrated that APα functioned as a neurotrophic factor for human, rat, and mouse neural progenitor cells (Keller et al., 2004; Wang et al., 2005, 2010; Charalampopoulos et al., 2008) and augmented the number of cells in the hippocampus and reversed deficits in learning and memory in a mouse model for Alzheimer’s disease (3xTgAD, a triple transgenic with APPSwe, PS1M146V, tauP301L) (Wang et al., 2010; Chen et al., 2011; Singh et al., 2012), for review see Brinton (2013) and Irwin and Brinton (2014). In contrast, APα has been reported to inhibit the learning and memory when chronically treated for 3 months (Bengtsson et al., 2012, 2013) and the potential mechanisms for this discrepancy have been discussed elsewhere (Brinton, 2013; Wang, 2013; Irwin and Brinton, 2014). "
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    ABSTRACT: Reinstalling the neurobiological circuits to effectively change the debilitating course of neurodegenerative diseases is of utmost importance. This reinstallation requires generation of new cells which are able to differentiate into specific types of neurons and modification of the local environment suitable for integration of these new neurons into the neuronal circuits. Allopregnanolone (APα) seems to be involved in both of these processes, and therefore, is a potential neurotrophic agent. Loss of dopamine neurons in the substantia nigra (SN) is one of the main pathological features of Parkinson's and also in, at least, a subset of Alzheimer's patients. Therefore, reinstallation of the dopamine neurons in nigrostriatal tract is of unique importance for these neurodegenerative diseases. However, for the neurogenic status and the roles of allopregnanolone in the nigrostriatal tract, the evidence is accumulating and debating. This review summarizes recent studies regarding the neurogenic status in the nigrostriatal tract. Furthermore, special attention is placed on evidence suggesting that reductions in allopregnenalone levels are one of the major pathological features in PD and AD. This evidence has also been confirmed in brains of mice that were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or those bearing neurodegenerative mutations. Lastly, we highlight studies showing that allopregnanalone can augment the number of total cells and dopaminergic neurons via peripheral exogenous administration.
    Frontiers in Cellular Neuroscience 08/2014; 8:224. DOI:10.3389/fncel.2014.00224 · 4.29 Impact Factor
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    • "Increasing evidence indicates that altered cholesterol homeostasis is linked to neuropathologies including AD (Schumacher et al., 2004; Mellon et al., 2008; Brinton, 2013). In addition to the mechanism of action whereby Allo induces neurogenesis (Brinton, 2013), Allo regulates cholesterol homeostasis via mechanisms that increases liver-X-receptor (LXR) and pregnane-Xreceptor (PXR; Chen et al., 2011). LXR is a nuclear hormone receptor abundant in the brain, primarily expressed in glial cells and acts as a molecular sensor of cholesterol levels and initiates cholesterol clearance (Whitney et al., 2002; Jakobsson et al., 2012). "
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    Frontiers in Cellular Neuroscience 07/2014; 8:203. DOI:10.3389/fncel.2014.00203 · 4.29 Impact Factor
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