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 (3α-hydroxy-5α-pregnan-20-one), (APα) 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 [1]. Proliferative efficacy was determined by incorporation of BrdU and 3H-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 3β-hydroxy-5β-pregnan-20-one and related steroids did not increase 3H-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 APα 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 Alzheimers disease mice. The in vitro and in vivo neurogenic properties of APα coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of toxicity, are key elements required for developing APα as a neurogenic / regenerative therapeutic for restoration of neurons in victims of Alzheimers disease.
Keywords: Allopregnanolone, neurogenesis, hippocampus, cell cycle genes, L-type calcium channel, therapeutics
Current Alzheimer Research
Title: Preclinical Analyses of the Therapeutic Potential of Allopregnanolone to Promote Neurogenesis In Vitro and In Vivo in Transgenic Mouse Model of Alzheimers Disease
Volume: 3 Issue: 1
Author(s): Roberta D. Brinton and Jun M. Wang
Affiliation:
Keywords: Allopregnanolone, neurogenesis, hippocampus, cell cycle genes, L-type calcium channel, therapeutics
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 (3α-hydroxy-5α-pregnan-20-one), (APα) 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 [1]. Proliferative efficacy was determined by incorporation of BrdU and 3H-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 3β-hydroxy-5β-pregnan-20-one and related steroids did not increase 3H-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 APα 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 Alzheimers disease mice. The in vitro and in vivo neurogenic properties of APα coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of toxicity, are key elements required for developing APα as a neurogenic / regenerative therapeutic for restoration of neurons in victims of Alzheimers disease.
Export Options
About this article
Cite this article as:
Brinton D. Roberta and Wang M. Jun, Preclinical Analyses of the Therapeutic Potential of Allopregnanolone to Promote Neurogenesis In Vitro and In Vivo in Transgenic Mouse Model of Alzheimers Disease, Current Alzheimer Research 2006; 3 (1) . https://dx.doi.org/10.2174/156720506775697160
DOI https://dx.doi.org/10.2174/156720506775697160 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Combination Therapy for Multi-Target Manipulation of Secondary Brain Injury Mechanisms
Current Neuropharmacology Myalgic Encephalomyelitis: Symptoms and Biomarkers
Current Neuropharmacology A Comprehensive Review on Recent Developments in the Field of Biological Applications of Potent Pyrazolines Derived from Chalcone Precursors
Letters in Drug Design & Discovery Editorial [Hot Topic: ABC Transporters in Pharmacology/Physiology and Human Diseases (Guest Editor: Zhe-Sheng (Jason) Chen)]
Current Pharmaceutical Biotechnology Neuroprotection for Amyotrophic Lateral Sclerosis: Role of Stem Cells, Growth Factors, and Gene Therapy
Central Nervous System Agents in Medicinal Chemistry New Horizons in the Treatment of Neurological Disorders with Tailorable Gold Nanoparticles
Current Drug Metabolism NGS Technologies as a Turning Point in Rare Disease Research , Diagnosis and Treatment
Current Medicinal Chemistry Anti-Inflammatory Treatments for Chronic Diseases: A Review
Inflammation & Allergy - Drug Targets (Discontinued) Role of Mesenchymal Stem Cells in Dermal Repair in Burns and Diabetic Wounds
Current Stem Cell Research & Therapy Amantadine, Apomorphine and Zolpidem in the Treatment of Disorders of Consciousness
Current Pharmaceutical Design Serpin Regulation of Fibrinolytic System: Implications for Therapeutic Applications in Cardiovascular Diseases
Cardiovascular & Hematological Agents in Medicinal Chemistry Patent Selections:
Recent Patents on Inflammation & Allergy Drug Discovery The Effects of Hydroalcoholic Extract of Pinus eldarica on Hippocampal Tissue Oxidative Damage in Pentylenetetrazole-Induced Seizures in Rat
Current Nutrition & Food Science The Role of Peripheral Benzodiazepine Receptors (PBRs) in CNS Pathophysiology
Current Medicinal Chemistry Vitamin D Supplementation: A Promising Approach for the Prevention and Treatment of Strokes
Current Drug Targets Repetitive Transcranial Magnetic Stimulation to Treat Substance Use Disorders and Compulsive Behavior
CNS & Neurological Disorders - Drug Targets Parallel Computing for Brain Simulation
Current Topics in Medicinal Chemistry Subject Index To Volume 9
Current Medicinal Chemistry Transitional Polytherapy: Tricks of the Trade for Monotherapy to Monotherapy AED Conversions
Current Neuropharmacology Nutrition and Bone Health: Its Relationship to Osteoporosis
Current Nutrition & Food Science