书目名称 | Natural Product-based Synthetic Drug Molecules in Alzheimer‘s Disease | 副标题 | Therapeutic & Theran | 编辑 | Abha Sharma,Gyan Prakash Modi | 视频video | http://file.papertrans.cn/662/661888/661888.mp4 | 概述 | Examines natural products as source of novel drug against Alzheimer’s disease.Covers the role of metal homeostasis and oxidative stress in the pathogenesis of Alzheimer’s disease.Discusses the role of | 图书封面 |  | 描述 | This book illustrates the importance of natural products as the source for the development of novel drugs for the treatment of neurodegenerative disorders, including Alzheimer‘s disease. It also highlights the role of reactive oxygen species and altered metal homeostasis in the progression of Alzheimer’s disease and examines the potential of antioxidants and anti-chelating agents in the clinical intervention of neurodegenerative diseases. The book also discusses the role of neuroinflammation in the pathogenesis of Alzheimer’s disease. The chapters provide information about the drug targets, progress in the development of natural product-based therapeutics, biomarkers, fluorescent diagnostic tools, and theranostic for Alzheimer‘s disease. The book also provides information about the design and synthesis of natural product-based derivatives against the various targets of Alzheimer‘s disease including epigenetic targets and the metal dyshomeostasis hypothesis. Cutting across different disciplines, this book is a valuable source for neuroscientists, chemical biologists, pharmaceutical researchers, and synthetic biologists.. | 出版日期 | Book 2023 | 关键词 | Alzheimer’s disease; Antioxidant; Natural molecules; Biomarkers; Multi-target ligand | 版次 | 1 | doi | https://doi.org/10.1007/978-981-99-6038-5 | isbn_softcover | 978-981-99-6040-8 | isbn_ebook | 978-981-99-6038-5 | copyright | The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapor |
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Alzheimer’s Disease and Drug Targets |
Amit Kumar,Awesh Kumar Yadav |
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Alzheimer’s disease (AD) is among the neurodegenerative disorders mainly characterized by loss of memory is also termed as dementia. The primary mechanism is centered on the deposition of extracellular plaques, which are mainly composed of amyloid-β (Aβ). Also, the deposition of neurofibrillary tangles of phosphorylated tau proteins inside the neurons affects the longevity of neurons. The other factors like the formation of reactive oxygen species (ROS) and neuroinflammation have crucial roles in the development of AD. Moreover, the improper enzymatic processing of Aβ is thought to be a responsible factor for the deposition of insoluble Aβ plaques. However, the drugs which prolong the half-life of acetylcholine by inhibiting the activity of the acetylcholine esterase enzyme are administered for the management of AD. Unfortunately, these available drugs provide only symptomatic support, cause severe side effects, and may cause the death of patients. Hence, new agents are required to target the disease at different levels or more than one level for the management of AD. The published pieces of literature show that inhibition of Aβ formation, degradation or disaggregation of Aβ plaque
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Oxidative Stress and Metals in Alzheimer’s Disease |
Shaik Ayesha Fathima,Ranika Maurya,Saba Naqvi |
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Alzheimer’s disease (AD) is one of the progressive neurodegenerative disorders allied with genetic, lifestyle, and environmental factors and mainly affects the elderly population. Key pathological hallmarks of AD are extracellular depositions of beta-amyloid plaques, intracellular accumulation of neurofibrillary tangles (NFTs), and alterations in amyloid precursor protein (APP) gene, and it is clinically characterised by changes in cellular and molecular cascades of synaptic loss, cognitive dysfunctions, and neuronal death. Some evidences support the role of major biomarker candidates to induce AD, which are oxidative stress and metals, as brain is more prone to generate the reactive oxygen species (ROS) by different metal ions. Imbalance between free radicals and antioxidant defence system leads to cell apoptosis and dyshomeostasis of essential endogenous redox active metal ions in brain such as iron (Fe), copper (Cu), chromium (Cr), and cobalt (Co), and redox inactive metals like cadmium (Cd), arsenic (As), and lead (Pb) and inert metal zinc (Zn) show their toxic effects in Alzheimer’s disease. To overcome the toxic effects of metal-induced ROS, there must be enhancement of two m
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Neuroinflammation in Alzheimer’s Disease |
Santanu Kaity,Anoop Kumar |
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Alzheimer’s disease (AD) is one of the significant progressive disorders of the brain, which lead to the destruction of memory and cognitive power in elderly individuals. Mild-to-severe extent of neurodegeneration triggers AD in most cases. Patients with AD carry a higher chance of generation of dementia, memory loss, and gradual loss of basic intellect. According to a recent report, calcium dysfunction at the neuron level and microglia-mediated neuroinflammation are the leading causes of AD. The formation of amyloid plaques at the extracellular level and neurofibrillary tangles in the intracellular part of neurons is the most established AD hypothesis as explored by different research groups throughout the globe to date. However, the exact root cause of the disease pathogenesis is still unknown which has made the disease incurable. Multiple symptomatic treatment options exist for AD, but none of the existing and new drug candidates proved to have potent disease-curing activity. This chapter deals mainly with the role of neuroinflammation in the disease progression of AD. The effect of injury, immunity, infection, and aging on neuroinflammation is described in detail. Further, the
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Biomarkers for Alzheimer’s Disease |
Mareechika Gaddam,Esther Rani Motamarri,Abha Sharma |
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Alzheimer’s disease is a neurodegenerative disease, which affects intellectually is frequently observed in elderly generations and genetically linked individuals. The diagnosis of this disease is characterized by the presence of biomarkers such as amyloid beta (Aβ.), phosphorylated tau (P-tau), and total tau (t-tau) protein causing NFTs’ intercellularly interrupting synapse, which aids in transmitting the neuronal signals, thereby leading to memory loss and cognitive impairment failing to do basic tasks in daily life. Acquiring the diagnosis of this disease through the presence of biomarkers is categorized into two ways, invasive and noninvasive. The invasive way includes the collection of cerebrospinal fluid which is considered painful, but the advantage of this method is that it verifies the presence of the biomarkers accurately by taking into account its close association with the brain. This method is usually done at late stages for confirmation. The less painful or noninvasive ways include collecting samples from blood and ocular, olfactory, and oral fluids. These methods are in the preliminary stages of research that need further investigation to overcome methodological heter
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Fluorescent Organic Molecules as Diagnostic and Theranostic Tools for Alzheimer’s Disease |
Kondakamarla Imran,Yashasvi Anant Dhamapurkar,Abha Sharma |
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Diagnosis of Alzheimer’s disease (AD) is crucial especially for the complete comprehension of pathology and clinical therapy of the disorder, as well as in declining the severity of the diseased condition. There are two major biomarkers associated with AD. One is an accumulation of insoluble amyloid beta, which later on gets transformed to amyloid plaques in extracellular space, and the other one is an aggregation of hyperphosphorylated tau, which has the capability to form neurofibrillary tangles in the intracellular space of neurons. Massive research efforts and resources are currently being dedicated towards the development of tools and methodologies for the identification and measurement of biomarkers indicative of molecular alterations in the brain and imminent neurodegeneration. The latest literature is showing a great interest towards the invention of a single chemical agent to deliver diagnosis and therapy simultaneously, which is entitled as “theranostics”. A theranostic agent is one that has both therapeutic and diagnostic qualities. Unlike the typical therapeutic method, in which two distinct drugs serve as deputies to achieve two different objectives, theranostic agents
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Nanostructure-Based Molecules as Diagnostic and Theranostic Tools in Alzheimer’s Disease |
Teeja Suthar,Keerti Jain |
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Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive, continuous, and irreversible degeneration of structure and function of neurons, is a major cognitive dysfunction amongst elderly population. Drugs with different pharmacology have been developed and approved for the treatment of AD, but these treatments are not curative and merely provide symptomatic relief. Successful treatment of AD requires drug targeting to the central nervous system in effective therapeutic concentrations. Blood-brain barrier (BBB) is a major hurdle in transporting drugs to the brain. Nanostructure-based materials can cross the BBB by virtue of their very small size. Further, surface modification of these materials could aid in targeting the drugs to specific cells/organs, and to achieve higher drug concentrations at the required site. Nanostructure-based imaging modalities, therapeutic agents, and theranostics provide highly sensitive detection at molecular levels, optimal drug targeting, and combined effect. Recent advancements in the field of nanotechnology have enabled the combined delivery of diagnostic as well as therapeutic agents to remarkably improve the outcomes of A
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Approved Cholinesterase Inhibitor-Based Derivatives: Synthesis and Their Biological Evaluation |
Mange Ram Yadav,Prashant R. Murumkar,Karan Joshi,Rahul Barot,Rasana Yadav |
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Discovery of therapeutics for multifactorial diseases and disorders involving multiple pathophysiological pathways is still a challenge for the researchers. Alzheimer’s disease (AD) is one such disease that involves multiple largely ambiguous pathophysiological pathways, which makes it a challenging thrust area of research around the globe. The current approved drugs for the management of the disease include rivastigmine, donepezil, galantamine (all AChE inhibitors), and memantine (NMDA receptor antagonist). Furthermore, bulk of the research on AD focuses on multi-target directed ligand (MTDL) approach which involves combining together two or more distinct pharmacophores to obtain potent MTDLs. In this chapter, we have discussed synthesis and biological evaluation of the most active novel moieties developed on the basis of the existing anti-Alzheimer’s drugs reported in the last 5 years, along with the in silico overview of their interactions with the biological targets.
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Memantine-Based Derivatives: Synthesis and Their Biological Evaluation |
Vinod Kumar,Vijay Kumar,Naveen Kumar,Vinay Kumar,Kailash Jangid |
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Alzheimer’s disease (AD) is a chronic neurological disorder characterized by memory loss and cognitive decline. It is a multifactorial disease, and a number of hypotheses including glutamate hypothesis are associated with the initiation and progression of AD. The ionic glutamate receptors, mainly the N-methyl-D-aspartate receptors (NMDAR), are largely dependent on the single excitatory agonist glutamate. Glutamate is released for milliseconds at the synaptic ending to communicate with other neurons, allowing the nervous system to transmit complex motor commands and sensory information and to form thoughts and memories. Memantine is an open-channel, low-affinity, uncompetitive antagonist of NMDA receptors. It was found that the physiological receptor functions of NMDAR were unhindered by memantine and selectively block ion channels under pathological conditions, and thus maintain an optimal level of NMDA. Memantine has emerged as a promising therapeutic approach for AD. This chapter explores various methodologies for the synthesis of memantine and its pharmacological properties. The chapter also describes selective action of memantine on NMDAR and recent advancements in the field of
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Huperzine-Based Derivatives: Design, Synthesis, and Anti-Alzheimer Activity |
Vedika G. Dadlani,Harshal Ashok Pawar,Pushpendra K. Tripathi |
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Alzheimer’s disease (AD) is a progressive illness of the nervous system typified by degenerative cognitive disability with challenging behavioural changes and dwindling physical activities for day-to-day living and remains one of the major reasons of dementia. As per the worldwide status report released by World Health Organization, the numbers of people with dementia will double every 20 years, reaching about 140 million in 2050. The currently used drugs for AD include galantamine, rivastigmine, and donepezil. These slow the progression of the disease or help to control cognitive and behavioural changes. Recently, aducanumab has been approved as a disease modifying drug targeting beta-amyloid and helps to reduce brain lesions. Another drug, memantine, is effective in regulating levels of glutamate, leading to brain cell death. Thus, the future involves multifunctional and targeted approaches, and multipotent naturally occurring agents have recently drawn attention in this regard. Huperzine A, derived from . is one amongst these. Chemically, it is an alkaloid containing quinolizidine with good potency and selectivity and reversible inhibition of acetylcholinesterase. Many analogs o
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Polyphenol: Development of Polyphenol-Inspired Derivatives Targeting Pathological Factors of AD |
Bhanuranjan Das,Anurag T. K. Baidya,Rajnish Kumar |
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Alzheimer’s disease (AD) is the most common type of dementia having a complex pathophysiology with no disease modifying treatments available in clinics. Polyphenolic compounds, a class of natural plant compounds, have been extensively studied for their potential therapeutic use in AD. The neuroprotective, antioxidant, as well as anti-inflammatory properties exhibited by these compounds are important in the treatment and management of AD. Phenolic compounds can inhibit the formation and aggregation of toxic proteins that are implicated in the disease, as well as promote their clearance from the brain. The anti-inflammatory effects of phenolic compounds are significant because chronic inflammation in the brain is thought to contribute to the development and advancement of AD. Additionally, phenolic compounds have been shown to improve cerebral blood flow and enhance neuronal signaling, which can help to improve cognitive function in AD patients. Due to their potential therapeutic efficacy, polyphenols are a key focus in medicinal chemistry for designing multi-targeted as well as single-targeted drug ligands against different therapeutic targets of AD. In this chapter, we have aimed t
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Flavonoid-Based Derivatives for Modulating Various Targets of Alzheimer’s Disease |
Jyoti Pandey |
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Alzheimer’s disease (AD), an advanced multifactorial neurodegenerative disease mainly accompanied by cognitive impairment, is the most conversant form of dementia. Contemporary studies have shown that inhibition of oxidative stress and target enzymes such as cholinesterase, β-secretase, monoamine oxidase, inhibition of hyperphosphorylation of tau protein and aggregation of amyloid-β plagues, inflammatory responses and unfolded protein responses perform a vital role in AD genesis. Flavonoids are polyphenol structured neuroprotecting agents, naturally found in plants and have imperative protective effects against neural dysfunction and injuries. Exhaustive research work has been performed on flavonoids of natural origin and its derivatives, to obtain effective drugs/therapy for AD control. This review is mainly focusing on the flavonoid derivatives which have been suggested to have anti-AD effects and may be utilized for reducing the risk and used for the effective treatment of AD.
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Vitamin-Based Derivatives for the Management of Alzheimer’s Disease |
Tanmaykumar Varma,Pradnya Kamble,Madhavi Kumari,Vineet Diwakar,Prabha Garg |
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Vitamins are organic compounds; they help in the regulation of many bodily functions like cell proliferation and differentiation, immunological response, and metabolism. A deficiency of these molecules can cause severe medical conditions, i.e., beriberi, xerophthalmia, scurvy, Crohn’s disease, and others. Furthermore, studies have shown that vitamin deficiency might lead to many neuronal dysfunctions, even hampering the growth of neurons. This chapter explores the role of vitamins and their derivatives in the pathology of Alzheimer’s disease. Alzheimer’s disease is a multifactorial neurodegenerative disease, and the cause of this disease is still unknown. However, several hypotheses try to explain the aetiology of the disease, such as Aβ hypothesis, metal ion hypothesis, calcium homeostasis, cholinergic hypothesis, tau propagation, etc. Scientific literature reports several derivatives that show potential to treat Alzheimer’s disease. Primarily these compounds act on nuclear receptors to activate ADAM10, inhibiting AChE or BuChE, neutralisation of ROS, inhibition of GSK-3, and amyloid-beta aggregation. Moreover, some can easily pass the BBB, which is crucial in targeting neurologic
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Metal Chelators as a Potential Therapeutic Agent for Alzheimer’s Disease |
Bhaskar Dewangan,Kunal Kumar,Amit Kumar,Praveen Reddy Bodhe,Sunita Beni,Bichismita Sahu |
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Alzheimer’s disease (AD) is a neurological condition that causes behavioural abnormalities and a progressive decline in intellectual abilities. In the brain, metal ions equilibria are essential for appropriate brain functioning, while dyshomeostasis of free metal ions is associated with Alzheimer’s disease. In the brain, dysregulated metal ions trigger various responses, such as promoting Aβ. aggregation, tau hyperphosphorylation, oxidative stress, and disruption of organelles, which leads to autophagic failure. Approved drugs for AD only have palliative effects. Thus, potential molecules with contrasting features, such as chelating agents and metal-based medicines, have been proposed to act on various molecular targets to treat AD. This chapter aims to highlight the various applications and current advancements of metal-based medications, including metal complexes and metal-chelating agents, as potential therapeutic agents for treating AD.
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Ferroptosis Modulators: A Potential Therapeutic Target in Alzheimer’s Disease |
Gourav Singh,Nishant Kumar Rana,Indubhusan Mishra,Gyan Prakash Modi |
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The most commonly known dementia, i.e., Alzheimer’s disease (AD) occurs in older age people and it is an irreversible neurodegenerative disorder of the brain that is primarily regarded as a decline in thinking and independence in daily activities. It is well documented that the disease development starts the years before the warning signs are evidenced and at that point most treatments become ineffective. Over a long time, vascular risk factors have been connected with cognitive decline and higher risk of AD through increased tau and cerebral amyloid β (Aβ) aggregates. Unlike programmed cell fate to death, ferroptosis is oxidative stress or aggregation of lipid peroxide and iron-reliant cell death associated with AD. The exact mechanism of action of ferroptosis in AD, related pathways, and differentially expressed genes need to be widely investigated. Ferroptosis hallmarks such as high levels of iron level, oxidative stress, and accumulation of lipid peroxides were investigated in the AD brain. Further, it was noticed that the development of neurofibrillary tangles and Aβ plaques are associated with iron burden in AD mice models. Here, we summarize the recent development of a ferro
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