Abstract
The prevalence of Alzheimer’s disease (AD) in the elderly is growing rapidly worldwide, and the deteriorating clinical course of AD places a heavy burden on both the patients and their families. Early detection and intervention of mild cognitive impairment in the early phase of AD is vital for the purpose of improving the cognitive performance of patients and preventing the existing deficits from worsening. However, the main compounds currently used to treat early AD, acetylcholinesterase inhibitors (AChEIs), are unsatisfactory in efficacy and safety. Moreover, evidence indicates that AChEIs are ineffective in treating AD at extremely early stages, which implies that mechanisms other than those targeted by AChEIs underlie the pathogenesis of AD. Dysfunctional glutamatergic neurotransmission, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been reported to play a role in the pathophysiology of AD. The NMDA receptor (NMDAR) regulates synaptic plasticity, memory, and cognition, and the attenuation of NMDAR-mediated neurotransmission can result in impaired neuroplasticity and cognitive deficits in the aging brain. Furthermore, NMDARs also interact with amyloid beta peptide/amyloid precursor protein and tau protein, whose production represents the main manifestations of AD. In this paper, we review the evidence supporting NMDA dysfunction in both animal models of AD and patients afflicted with AD, and we also review the literature that suggests that NMDA-enhancing agents such as glycine and D-cycloserine can improve cognitive functions. The benefits and limitations of NMDAR antagonists that can diminish the excitatory neurotoxicity triggered by glutamate are also addressed in relation to AD. We propose that enhancing glutamatergic neurotransmission by activating the NMDAR may be effective in treating the cognitive decline that occurs in AD. Prospective studies on AD in which NMDA-enhancing agents are used are required to verify this hypothesis and confirm the long-term efficacy and safety of the treatment agents.
Keywords: Glutamate, NMDA, Alzheimer’s disease, mild cognitive impairment.
Current Pharmaceutical Design
Title:NMDA Neurotransmission Dysfunction in Mild Cognitive Impairment and Alzheimers Disease
Volume: 20 Issue: 32
Author(s): Chieh-Hsin Lin, Yu-Jhen Huang, Chun-Jung Lin, Hsien-Yuan Lane and Guochuan E. Tsai
Affiliation:
Keywords: Glutamate, NMDA, Alzheimer’s disease, mild cognitive impairment.
Abstract: The prevalence of Alzheimer’s disease (AD) in the elderly is growing rapidly worldwide, and the deteriorating clinical course of AD places a heavy burden on both the patients and their families. Early detection and intervention of mild cognitive impairment in the early phase of AD is vital for the purpose of improving the cognitive performance of patients and preventing the existing deficits from worsening. However, the main compounds currently used to treat early AD, acetylcholinesterase inhibitors (AChEIs), are unsatisfactory in efficacy and safety. Moreover, evidence indicates that AChEIs are ineffective in treating AD at extremely early stages, which implies that mechanisms other than those targeted by AChEIs underlie the pathogenesis of AD. Dysfunctional glutamatergic neurotransmission, particularly that mediated by the N-methyl-D-aspartate (NMDA) receptor, has been reported to play a role in the pathophysiology of AD. The NMDA receptor (NMDAR) regulates synaptic plasticity, memory, and cognition, and the attenuation of NMDAR-mediated neurotransmission can result in impaired neuroplasticity and cognitive deficits in the aging brain. Furthermore, NMDARs also interact with amyloid beta peptide/amyloid precursor protein and tau protein, whose production represents the main manifestations of AD. In this paper, we review the evidence supporting NMDA dysfunction in both animal models of AD and patients afflicted with AD, and we also review the literature that suggests that NMDA-enhancing agents such as glycine and D-cycloserine can improve cognitive functions. The benefits and limitations of NMDAR antagonists that can diminish the excitatory neurotoxicity triggered by glutamate are also addressed in relation to AD. We propose that enhancing glutamatergic neurotransmission by activating the NMDAR may be effective in treating the cognitive decline that occurs in AD. Prospective studies on AD in which NMDA-enhancing agents are used are required to verify this hypothesis and confirm the long-term efficacy and safety of the treatment agents.
Export Options
About this article
Cite this article as:
Lin Chieh-Hsin, Huang Yu-Jhen, Lin Chun-Jung, Lane Hsien-Yuan and Tsai E. Guochuan, NMDA Neurotransmission Dysfunction in Mild Cognitive Impairment and Alzheimers Disease, Current Pharmaceutical Design 2014; 20 (32) . https://dx.doi.org/10.2174/1381612819666140110115603
DOI https://dx.doi.org/10.2174/1381612819666140110115603 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Selenium in the Therapy of Neurological Diseases. Where is it Going?
Current Neuropharmacology Flavones from Root of Scutellaria Baicalensis Georgi: Drugs of the Future in Neurodegeneration?
CNS & Neurological Disorders - Drug Targets Neural Stem Cell Transplantation and CNS Diseases
CNS & Neurological Disorders - Drug Targets Copper Status Abnormalities and How to Measure Them in Neurodegenerative Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Modulation of Neuro-Inflammation and Vascular Response by Oxidative Stress Following Cerebral Ischemia-Reperfusion Injury
Current Medicinal Chemistry Patent Selections
Recent Patents on Biotechnology The Overlapping Syndromes of the Pick Complex
Current Alzheimer Research Role of FK506 Binding Proteins in Neurodegenerative Disorders
Current Medicinal Chemistry A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease
Current Medicinal Chemistry <i>In-silico</i> Prediction of the Beta-carboline Alkaloids Harmine and Harmaline as Potent Drug Candidates for the Treatment of Parkinson’s disease
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Oxidative Stress During Myocardial Ischaemia and Heart Failure
Current Pharmaceutical Design Solvent-Free Synthesis of 4,5-Dihydropyrano[c]chromene Derivatives Over TiO<sub>2</sub> Nanoparticles as an Economical and Efficient Catalyst
Current Catalysis Meet Our Regional Editor
CNS & Neurological Disorders - Drug Targets AMPA Glutamate Receptors and Neuropathic Pain
Mini-Reviews in Medicinal Chemistry Recombinant Human Insulin-Like Growth Factor-1: A New Cardiovascular Disease Treatment Option?
Cardiovascular & Hematological Agents in Medicinal Chemistry Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application
Current Molecular Pharmacology The Variable Presentations of Glycogen Storage Disease Type IV: A Review of Clinical, Enzymatic and Molecular Studies
Current Molecular Medicine Exploring Multiple Sclerosis (MS) and Amyotrophic Lateral Scler osis (ALS) as Neurodegenerative Diseases and their Treatments: A Review Study
Current Topics in Medicinal Chemistry The Insulin-like Growth Factor-1 Axis and its Potential as a Therapeutic Target in Central Nervous System (CNS) Disorders
Central Nervous System Agents in Medicinal Chemistry Effect of Drugs in Cells and Tissues by NMR Spectroscopy
Current Topics in Medicinal Chemistry