Abstract
Cholinesterase inhibitors (ChEIs) were introduced in the therapy of Alzheimer Disease (AD) in the nineteen nineties with great expectations. The hopes and large interest raised by these drugs are well demonstrated by 12,000 references listed by PubMed under ‘ChEI’ for 1995-2007. The list is reduced to 2500 if we confine ourselves to ‘ChEIs and dementia’. Of them, about 500 were published in the last two years. Whereas an increase in brain acetylcholine and an improvement of cognitive deficits have been consistently demonstrated in animal models of AD, from aging rats to transgenic mice, the clinical effectiveness of ChEIs has been and is still a matter of contrasting opinions. These range from the negative conclusions of the AD2000 trial on donepezil, claiming that it is not cost effective, with benefits below a minimally relevant threshold, to the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are efficacious for mild to moderate AD, irrespective of their different selectivity for acetyl- (AChE) and butyrylcholinesterase (BuChE). The possibility that ChEIs may exert their effects through mechanisms beyond cholinesterase inhibition has been envisaged. However, according to the information presented in this review, the “classical” ChEIs, donepezil, rivastigmine and galantamine, show no pharmacological actions beyond cholinesterase inhibition which may play an important role in their therapeutic efficacy. The diverging opinions on clinical efficacy do not discourage from developing new ChEIs, and particularly the so called multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but other indications for these drugs may be considered, including vascular dementia, mild cognitive impairment, and the ethically sensitive improvement of memory and learning in healthy subjects.
Keywords: Acetylcholine, Acetylcholinesterase, Alzheimer therapy, β-Amyloid, novel cholinesterase inhibitors
Current Alzheimer Research
Title: Cholinesterase Inhibitors and Beyond
Volume: 6 Issue: 2
Author(s): Giancarlo Pepeu and Maria Grazia Giovannini
Affiliation:
Keywords: Acetylcholine, Acetylcholinesterase, Alzheimer therapy, β-Amyloid, novel cholinesterase inhibitors
Abstract: Cholinesterase inhibitors (ChEIs) were introduced in the therapy of Alzheimer Disease (AD) in the nineteen nineties with great expectations. The hopes and large interest raised by these drugs are well demonstrated by 12,000 references listed by PubMed under ‘ChEI’ for 1995-2007. The list is reduced to 2500 if we confine ourselves to ‘ChEIs and dementia’. Of them, about 500 were published in the last two years. Whereas an increase in brain acetylcholine and an improvement of cognitive deficits have been consistently demonstrated in animal models of AD, from aging rats to transgenic mice, the clinical effectiveness of ChEIs has been and is still a matter of contrasting opinions. These range from the negative conclusions of the AD2000 trial on donepezil, claiming that it is not cost effective, with benefits below a minimally relevant threshold, to the NICE appraisal of 2007 declaring that donepezil, rivastigmine, galantamine are efficacious for mild to moderate AD, irrespective of their different selectivity for acetyl- (AChE) and butyrylcholinesterase (BuChE). The possibility that ChEIs may exert their effects through mechanisms beyond cholinesterase inhibition has been envisaged. However, according to the information presented in this review, the “classical” ChEIs, donepezil, rivastigmine and galantamine, show no pharmacological actions beyond cholinesterase inhibition which may play an important role in their therapeutic efficacy. The diverging opinions on clinical efficacy do not discourage from developing new ChEIs, and particularly the so called multifunctional ChEIs. They represent the future of the cholinergic therapy for AD but other indications for these drugs may be considered, including vascular dementia, mild cognitive impairment, and the ethically sensitive improvement of memory and learning in healthy subjects.
Export Options
About this article
Cite this article as:
Pepeu Giancarlo and Giovannini Grazia Maria, Cholinesterase Inhibitors and Beyond, Current Alzheimer Research 2009; 6 (2) . https://dx.doi.org/10.2174/156720509787602861
DOI https://dx.doi.org/10.2174/156720509787602861 |
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
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
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...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
-
The Role of Oxidative Stress in Cerebral Aneurysm Formation and Rupture
Current Neurovascular Research RAGE: A Multi-Ligand Receptor Unveiling Novel Insights in Health and Disease
Current Medicinal Chemistry Serum Amyloid Beta Peptides in Patients with Dementia and Age-Matched Non-Demented Controls as Detected by Surface-Enhanced Laser Desorption Ionisation-Time of Flight Mass Spectrometry (SELDI-TOF MS)
Current Clinical Pharmacology Economic Aspects on Drug Therapy of Dementia
Current Pharmaceutical Design A Role of the Parasympathetic Nervous System in Cognitive Training
Current Alzheimer Research The “Aged Garlic Extract” (AGE) and One of its Active Ingredients S-Allyl-LCysteine (SAC) as Potential Preventive and Therapeutic Agents for Alzheimer's Disease (AD)
Current Medicinal Chemistry Heme Oxygenase-1 Dysregulation in the Brain: Implications for HIVAssociated Neurocognitive Disorders
Current HIV Research How Immune-inflammatory Processes Link CNS and Psychiatric Disorders: Classification and Treatment Implications
CNS & Neurological Disorders - Drug Targets Inflammation and Anemia
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry NO to Breast: When, Why and Why Not?
Current Pharmaceutical Design Inhibition of Dipeptidyl Peptidase-4 (DPP-4): A Target to Treat Type 2 Diabetes
Current Enzyme Inhibition Histamine H3 Antagonists for Treatment of Cognitive Deficits in CNS Diseases
Current Topics in Medicinal Chemistry Natural Products Based Ayurvedic Formulations: Chemical Cons tituents and Treatment in Neurodegenerative Disordersǂ
Mini-Reviews in Organic Chemistry Editorial (Thematic Issue: Phytochemicals for Human Diseases: An Update)
Current Pharmaceutical Biotechnology Quantitative μPET Imaging of Cerebral Glucose Metabolism and Amyloidosis in the TASTPM Double Transgenic Mouse Model of Alzheimer’s Disease
Current Alzheimer Research Safety of Systemic Biologic Agents in the Treatment of Non-malignant Skin Disorders
Current Drug Safety Anticoagulation in Patients with Heparin-Induced Thrombocytopenia undergoing Percutaneous Coronary Angiography and Interventions
Current Pharmaceutical Design Somatostatin and Cognitive Function in Neurodegenerative Disorders
Mini-Reviews in Medicinal Chemistry Subject Index to Volume 4
Current Drug Targets - Cardiovascular & Hematological Disorders “Micromanaging” Glioblastoma Multiforme: The Potential of MicroRNAs, Circular RNAs, and the Hippo Pathway as Novel Treatment Strategies
Current Neurovascular Research