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Neuropharmacology Jun 2021Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral... (Review)
Review
Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders.
Topics: Alzheimer Disease; Antioxidants; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Galantamine; Humans; Receptors, N-Methyl-D-Aspartate; Rivastigmine
PubMed: 33035532
DOI: 10.1016/j.neuropharm.2020.108352 -
Frontiers in Aging Neuroscience 2023Alzheimer's disease (AD) is the most common chronic neurodegenerative disease worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, and mental... (Review)
Review
Alzheimer's disease (AD) is the most common chronic neurodegenerative disease worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, and mental symptoms, such as behavioral abnormalities; all of which place a significant psychological and economic burden on the patients' families. No specific drugs are currently available for the treatment of AD, and the current drugs for AD only delay disease onset and progression. The pathophysiological basis of AD involves abnormal deposition of beta-amyloid protein (Aβ), abnormal tau protein phosphorylation, decreased activity of acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, and multi-targets. The US Food and Drug Administration (FDA) has approved five drugs for clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, and lecanemab. We have focused on the newer drugs that have undergone clinical trials, most of which have not been successful as a result of excessive clinical side effects or poor efficacy. Although aducanumab received rapid approval from the FDA on 7 June 2021, its long-term safety and tolerability require further monitoring and confirmation. In this literature review, we aimed to explore the possible pathophysiological mechanisms underlying the occurrence and development of AD. We focused on anti-Aβ and anti-tau drugs, mitochondria-targeting and multi-targets, commercially available drugs, bottlenecks encountered in drug development, and the possible targets and therapeutic strategies for future drug development. We hope to present new concepts and methods for future drug therapies for AD.
PubMed: 37600514
DOI: 10.3389/fnagi.2023.1206572 -
Molecules (Basel, Switzerland) May 2022Neurodegenerative diseases, among which one of the more common is Alzheimer's disease, are the one of the biggest global public health challenges facing our generation... (Review)
Review
Neurodegenerative diseases, among which one of the more common is Alzheimer's disease, are the one of the biggest global public health challenges facing our generation because of the increasing elderly population in most countries. With the growing burden of these diseases, it is essential to discover and develop new treatment options capable of preventing and treating them. Neurodegenerative diseases, among which one of the most common is Alzheimer's disease, are a multifactorial disease and therefore demand multiple therapeutic approaches. One of the most important therapeutic strategies is controlling the level of acetylcholine-a neurotransmitter in cholinergic synapses-by blocking the degradation of acetylcholine using acetylcholinesterase inhibitors such as tacrine, galantamine, donepezil and rivastigmine. However, these drugs can cause some adverse side effects, such as hepatotoxicity and gastrointestinal disorder. Thus, the search for new, more effective drugs is very important. In the last few years, different active constituents from plants have been tested as potential drugs in neurodegenerative disease therapy. The availability, lower price and less toxic effects of herbal medicines compared with synthetic agents make them a simple and excellent choice in the treatment of neurodegenerative diseases. The empirical approach to discovering new drugs from the systematic screening of plant extracts or plant-derived compounds is still an important strategy when it comes to finding new biologically active substances. The aim of this review is to identify new, safe and effective compounds that are potential candidates for further in vivo and clinical tests from which more effective drugs for the treatment of Alzheimer's disease could be selected. We reviewed the methods used to determine anti-Alzheimer's disease activity. Here, we have discussed the relevance of plant-derived compounds with in vitro activity. Various plants and phytochemical compounds have shown different activity that could be beneficial in the treatment of Alzheimer's disorders. Most often, medicinal plants and their active components have been investigated as acetylcholinesterase and/or butyrylcholinesterase activity inhibitors, modifiers of β-amyloid processing and antioxidant agents. This study also aims to highlight species with assessed efficacy, usable plant parts and the most active plant components in order to identify species and compounds of interest for further study. Future research directions are suggested and recommendations made to expand the use of medicinal plants, their formulations and plant-derived active compounds to prevent, mitigate and treat Alzheimer's disease.
Topics: Acetylcholine; Acetylcholinesterase; Aged; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Neurodegenerative Diseases; Phytochemicals; Plants, Medicinal
PubMed: 35630702
DOI: 10.3390/molecules27103222 -
International Journal of Molecular... Jan 2023Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the "one drug-multiple targets" strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity.
Topics: Humans; Tacrine; Alzheimer Disease; Cholinesterase Inhibitors; Amyloid beta-Peptides; Chemical and Drug Induced Liver Injury; Acetylcholinesterase
PubMed: 36675233
DOI: 10.3390/ijms24021717 -
Oxidative Medicine and Cellular... 2022Tacrine is a drug used in the treatment of Alzheimer's disease as a cognitive enhancer and inhibitor of the enzyme acetylcholinesterase (AChE). However, its clinical... (Review)
Review
Tacrine is a drug used in the treatment of Alzheimer's disease as a cognitive enhancer and inhibitor of the enzyme acetylcholinesterase (AChE). However, its clinical application has been restricted due to its poor therapeutic efficacy and high prevalence of detrimental effects. An attempt was made to understand the molecular mechanisms that underlie tacrine and its analogues influence over neurotherapeutic activity by focusing on modulation of neurogenesis, neuroinflammation, endoplasmic reticulum stress, apoptosis, and regulatory role in gene and protein expression, energy metabolism, Ca homeostasis modulation, and osmotic regulation. Regardless of this, analogues of tacrine are considered as a model inhibitor of cholinesterase in the therapy of Alzheimer's disease. The variety both in structural make-up and biological functions of these substances is the main appeal for researchers' interest in them. A new paradigm for treating neurological diseases is presented in this review, which includes treatment strategies for Alzheimer's disease, as well as other neurological disorders like Parkinson's disease and the synthesis and biological properties of newly identified versatile tacrine analogues and hybrids. We have also shown that these analogues may have therapeutic promise in the treatment of neurological diseases in a variety of experimental systems.
Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Humans; Structure-Activity Relationship; Tacrine
PubMed: 36035218
DOI: 10.1155/2022/7252882 -
Current Neuropharmacology 2019Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of... (Review)
Review
Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as a model inhibitor of cholinesterases in the therapy of Alzheimer's disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer's disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist of a new paradigm to treat Alzheimer's disease. We have also reported potential of these analogues in the treatment of Alzheimer's diseases in various experimental systems.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinergic Neurons; Cholinesterase Inhibitors; Humans; Tacrine
PubMed: 29651948
DOI: 10.2174/1570159X16666180412091908 -
Dialogues in Clinical Neuroscience Jun 2000Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an undertreated and under-recognized disease that is becoming a major public...
Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an undertreated and under-recognized disease that is becoming a major public health problem. The last decade has witnessed a steadily increasing effort directed at discovering the etiology of the disease and developing pharmacological treatment. Recent developments include improved clinical diagnostic guidelines and improved treatment of both cognitive disturbance and behavioral problems. Symptomatic treatment mainly focusing on cholinergic therapy has been clinically evaluated by randomized, double-blind, placebo-controlled, parallel-group studies measuring performance-based tests of cognitive function, activities of daily living, and behavior. Cholinesterase inhibitors, including donepezil, tacrine, rivastigmine, and galantamine are the recommended treatment of cognitive disturbance in patients with Alzheimer's disease. The role of estrogen replacement, anti-inflammatory agents, and antioxidants is controversial and needs further study. Antidepressants, antipsychotics, mood stabilizers, anxiolytics, and hypnotics are used for the treatment of behavioral disturbance. Future directions in the research and treatment of patients with Alzheimer's disease include: applying functional brain imaging techniques in early diagnosis and evaluation of treatment efficacy; development of new classes of medications working on different neurotransmitter systems (cholinergic, glutamatergic, etc), both for the treatment of the cognitive deficit and the treatment of the behavioral disturbances; and developing preventive methods (amyloid p-peptide immunizations and inhibitors of β-secretase and γ-secretase).
PubMed: 22034442
DOI: 10.31887/DCNS.2000.2.2/asschachter -
International Journal of Molecular... Aug 2020Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique... (Review)
Review
Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique structure with two binding sites connected by a gorge region, and it has historically been the main pharmacological target for treatment of Alzheimer's disease. Given the large projected increase in Alzheimer's disease cases in the coming decades and its complex, multifactorial nature, new drugs that target multiple aspects of the disease at once are needed. Tacrine, the first acetylcholinesterase inhibitor used clinically but withdrawn due to hepatotoxicity concerns, remains an important starting point in research for the development of multitarget-directed acetylcholinesterase inhibitors. This review highlights tacrine-based, multitarget-directed acetylcholinesterase inhibitors published in the literature since 2015 with a specific focus on merged compounds (i.e., compounds where tacrine and a second pharmacophore show significant overlap in structure). The synthesis of these compounds from readily available starting materials is discussed, along with acetylcholinesterase inhibition data, relative to tacrine, and structure activity relationships. Where applicable, molecular modeling, to elucidate key enzyme-inhibitor interactions, and secondary biological activity is highlighted. Of the numerous compounds identified, there is a subset with promising preliminary screening results, which should inspire further development and future research in this field.
Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Drug Discovery; Humans; Liver; Neuroprotective Agents; Tacrine
PubMed: 32825138
DOI: 10.3390/ijms21175965