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
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.
- "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. "
Article: Food and Chemical Toxicology[Show abstract] [Hide abstract]
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.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). "
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). "
ABSTRACT: Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer’s disease that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.Frontiers in Cellular Neuroscience 07/2014; 8:203. DOI:10.3389/fncel.2014.00203 · 4.29 Impact Factor
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