Abstract
Down syndrome (DS) is the most common genetically defined cause of intellectual disability and accounts for over 50% of the cases of Alzheimer-type dementia in persons younger than 50 years of age. At present, no pharmacotherapy aimed at counteracting either the neurodevelopmental or the neurodegenerative component of this genetic disorder has been approved. Recent preclinical and clinical work on the N-methyl-D-aspartate (NMDA) receptor antagonist memantine give us some reason for optimism, at least in relation to the potential for a partial pharmacological improvement of hippocampus dependent memory deficits associated with DS. Here, we will review briefly the roles of NMDA receptors in health and disease, including the glutamatergic hypothesis for Alzheimer disease. Then, we will describe the basis for a glutamatergic hypothesis for DS, by reviewing the available preclinical evidence and assessing potential molecular mechanisms for NMDA receptor dysfunction in DS. A short description of the first two clinical trials of memantine in young and older adults with DS will follow. We will conclude by reviewing three caregiver reports from our recent clinical study and some lessons we have learned designing and conducting the first translational study in the field of DS to arise directly from experimental results in animal models.
Keywords: Down syndrome, Alzheimer disease, Trisomy 21, Ts65Dn mouse, Memantine, N-methyl-D-aspartate receptor, Long-term potentiation, Long-term depression.
CNS & Neurological Disorders - Drug Targets
Title:The Glutamatergic Hypothesis for Down Syndrome: The Potential Use of N-Methyl-D-Aspartate Receptor Antagonists to Enhance Cognition and Decelerate Neurodegeneration
Volume: 13 Issue: 1
Author(s): Alberto C.S. Costa
Affiliation:
Keywords: Down syndrome, Alzheimer disease, Trisomy 21, Ts65Dn mouse, Memantine, N-methyl-D-aspartate receptor, Long-term potentiation, Long-term depression.
Abstract: Down syndrome (DS) is the most common genetically defined cause of intellectual disability and accounts for over 50% of the cases of Alzheimer-type dementia in persons younger than 50 years of age. At present, no pharmacotherapy aimed at counteracting either the neurodevelopmental or the neurodegenerative component of this genetic disorder has been approved. Recent preclinical and clinical work on the N-methyl-D-aspartate (NMDA) receptor antagonist memantine give us some reason for optimism, at least in relation to the potential for a partial pharmacological improvement of hippocampus dependent memory deficits associated with DS. Here, we will review briefly the roles of NMDA receptors in health and disease, including the glutamatergic hypothesis for Alzheimer disease. Then, we will describe the basis for a glutamatergic hypothesis for DS, by reviewing the available preclinical evidence and assessing potential molecular mechanisms for NMDA receptor dysfunction in DS. A short description of the first two clinical trials of memantine in young and older adults with DS will follow. We will conclude by reviewing three caregiver reports from our recent clinical study and some lessons we have learned designing and conducting the first translational study in the field of DS to arise directly from experimental results in animal models.
Export Options
About this article
Cite this article as:
Costa C.S. Alberto, The Glutamatergic Hypothesis for Down Syndrome: The Potential Use of N-Methyl-D-Aspartate Receptor Antagonists to Enhance Cognition and Decelerate Neurodegeneration, CNS & Neurological Disorders - Drug Targets 2014; 13 (1) . https://dx.doi.org/10.2174/18715273113126660183
DOI https://dx.doi.org/10.2174/18715273113126660183 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...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
Related Articles
-
Impact of a Clinical Decision Support Tool on Dementia Diagnostics in Memory Clinics: The PredictND Validation Study
Current Alzheimer Research Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, α -Synuclein Synthesis, Interleukin-1β Release, and Cholinergic Action.
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Let Them Eat Cake
Current Nutrition & Food Science Recent Advances in the Discovery of α1-Adrenoceptor Agonists
Current Topics in Medicinal Chemistry Current Status and Perspectives in Ceramide-Targeting Molecular Medicine
Current Pharmaceutical Design Design and Synthesis of Dopaminergic Agonists
Current Medicinal Chemistry Reduced Alzheimer’s Disease Pathology by St. John’s Wort Treatment is Independent of Hyperforin and Facilitated by ABCC1 and Microglia Activation in Mice
Current Alzheimer Research Adiposity and Alzheimers Disease
Current Alzheimer Research Recent Patents on PCSK9: A New Target for Treating Hypercholesterolemia
Recent Patents on DNA & Gene Sequences Current and Future of Alzheimer's Therapy with the Best Approach
CNS & Neurological Disorders - Drug Targets Properties and Therapeutic Potential of Transient Receptor Potential Channels with Putative Roles in Adversity: Focus on TRPC5, TRPM2 and TRPA1
Current Drug Targets Proteomics Approaches to Understand Linkage Between Alzheimer’s Disease and Type 2 Diabetes Mellitus
CNS & Neurological Disorders - Drug Targets Brain: The Potential Diagnostic and Therapeutic Target for Glaucoma
CNS & Neurological Disorders - Drug Targets Treating Alzheimers Disease by Inactivating Bioactive Amyloid β Peptide
Current Alzheimer Research Patent Selections:
Recent Patents on CNS Drug Discovery (Discontinued) Design, Synthesis and Investigation of New Diphenyl Substituted Pyridazinone Derivatives as Both Cholinesterase and Aβ-Aggregation Inhibitors
Medicinal Chemistry Possible Mechanisms of Action of NSAIDs and Related Compounds that Modulate γ - Secretase Cleavage
Current Topics in Medicinal Chemistry The Mediterranean and other Dietary Patterns in Secondary Cardiovascular Disease Prevention: A Review
Current Vascular Pharmacology Valproic Acid Attenuates Neuronal Loss in the Brain of APP/PS1 Double Transgenic Alzheimer’s Disease Mice Model
Current Alzheimer Research The Ubiquitin Proteasome System as a Potential Target for the Treatment of Neurodegenerative Diseases
Current Pharmaceutical Design