Preclinical analyses of the therapeutic potential of allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's disease.
ABSTRACT Herein, we present data to support a preclinical proof of concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has demonstrated that the neuroactive progesterone metabolite, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural stem cells (hNSM) derived from the cerebral cortex . Proliferative efficacy was determined by incorporation of BrdU and (3)H-thymidine, FACS analysis of MuLV-GFP-labeled mitotic NPCs and quantification of total cell number. Allopregnanolone-induced proliferation was isomer and steroid specific, in that the stereoisomer 3beta-hydroxy-5beta-pregnan-20-one and related steroids did not increase (3)H-thymidine uptake. Immunofluorescent analyses for the NPC markers, nestin and Tuj1, indicated that newly formed cells were of neuronal lineage. Furthermore, microarray analysis of cell cycle genes and real time RT-PCR and western blot validation revealed that allopregnanolone increased the expression of genes which promote mitosis and inhibited the expression of genes that repress cell proliferation. Allopregnanolone-induced proliferation was antagonized by the voltage gated L-type calcium channel blocker nifedipine consistent with the finding that allopregnanolone induces a rapid increase in intracellular calcium in hippocampal neurons via a GABA type A receptor activated L-type calcium channel. Preliminary in vivo data indicate that APalpha for 24 hrs significantly increased neurogenesis in dentate gyrus, as determined by unbiased stereological analysis of BrdU positive cells, of 3-month-old male triple transgenic Alzheimer's disease mice. The in vitro and in vivo neurogenic properties of APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for restoration of neurons in victims of Alzheimer's disease.
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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 (AD) 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 · 4.18 Impact Factor
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ABSTRACT: Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids.Psychopharmacology 07/2014; DOI:10.1007/s00213-014-3673-4 · 3.99 Impact Factor
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ABSTRACT: Introduction: Neurosteroids are molecules that regulate physiological functions of the CNS. There is increasing evidence suggesting that impaired neurosteroid biosynthesis has been associated with distinct psychiatric disorders. This review summarizes data from studies that have investigated the relationship between progesterone (PROG) and psychiatric disorders as well as the mechanisms potentially involved in PROG-induced neuroprotection. Areas covered: The review covers the role of PROG and its metabolites in psychiatric disorders, focusing on results from preclinical and some clinical studies that support the relationship between alterations on PROG levels and pathophysiology of psychiatric illness. We also discussed the main mechanisms underlying the neuroprotective effects of PROG metabolites. Expert opinion: Our review points out the possible relationship between PROG and its metabolites and the pathophysiology of psychiatric disorders. Furthermore, both preclinical and clinical studies show that certain treatments (antidepressants or antipsychotics) may normalize the levels of PROG, suggesting that the amelioration of psychiatric symptoms may occur due to upregulation of PROG metabolites. Therefore, these results give support to new possibilities of treatment for patients with psychiatric symptoms from anxiety- and depressive-like behaviors to aggressive behaviors.Expert Opinion on Therapeutic Targets 03/2014; DOI:10.1517/14728222.2014.897329 · 4.90 Impact Factor