Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease.

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Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

Current Pharmaceutical Design ◽

10.2174/1381612826666201112144006 ◽

2020 ◽

Vol 26 ◽

Author(s):

Nimra Javaid ◽

Muhammad Ajmal Shah ◽

Azhar Rasul ◽

Zunera Chauhdary ◽

Uzma Saleem ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ellagic Acid ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Acetylcholinesterase Activity ◽

Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

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AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2018.45 ◽

2018 ◽

pp. 1-7

Author(s):

P. Novak ◽

N. Zilka ◽

M. Zilkova ◽

B. Kovacech ◽

R. Skrabana ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Phase 1 ◽

Primary Progressive Aphasia ◽

Tau Proteins ◽

Active Immunotherapy ◽

Tau Pathology

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

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Alzheimer’s Disease: Current and Future Treatments. A Review

International Journal of Medical Students ◽

10.5195/ijms.2014.85 ◽

2014 ◽

Vol 2 (2) ◽

pp. 56-63

Author(s):

Evelyn Chou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholinesterase Inhibitors ◽

Neurodegenerative Disorder ◽

Nmda Antagonists ◽

Disease Modifying Drugs ◽

Plaque Deposition ◽

The Future ◽

Disease Modifying ◽

Future Treatments

Alzheimer’s disease (AD) is a currently incurable neurodegenerative disorder whose treatment poses a big challenge. Proposed causes of AD include the cholinergic, amyloid and tau hypotheses. Current therapeutic treatments have been aimed at dealing with the neurotransmitter imbalance. These include cholinesterase inhibitors and N-Methyl-D-aspartate (NMDA) antagonists. However, current therapeutics have been unable to halt AD progression. Much research has gone into the development of disease-modifying drugs to interfere with the course of the disease. Approaches include secretase inhibition and immunotherapy aimed at reducing plaque deposition. However, these have not been successful in curing AD as yet. It is believed that the main reason why therapeutics have failed to work is that treatment begins too late in the course of the disease. The future of AD treatment thus appears to lie with prevention rather than cure. In this article, current therapeutics and, from there, the future of AD treatment are discussed.

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Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapy for Alzheimer’s Disease: Progress and Opportunity

Membranes ◽

10.3390/membranes11100796 ◽

2021 ◽

Vol 11 (10) ◽

pp. 796

Author(s):

Yi-An Chen ◽

Cheng-Hsiu Lu ◽

Chien-Chih Ke ◽

Ren-Shyan Liu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Extracellular Vesicle ◽

Synaptic Loss ◽

Molecular Machinery ◽

And Function ◽

Preclinical And Clinical Studies ◽

Ad Therapy

Alzheimer’s disease (AD), as a neurodegenerative disorder, is characterized by mass neuronal and synaptic loss and, currently, there are no successful curative therapies. Extracellular vesicles (EVs) are an emerging approach to intercellular communication via transferring cellular materials such as proteins, lipids, mRNAs, and miRNAs from parental cells to recipient cells, leading to the reprogramming of the molecular machinery. Numerous studies have suggested the therapeutic potential of EVs derived from mesenchymal stem cells (MSCs) in the treatment of AD, based on the neuroprotective, regenerative and immunomodulatory effects as effective as MSCs. In this review, we focus on the biology and function of EVs, the potential of MSC-derived EVs for AD therapy in preclinical and clinical studies, as well as the potent mechanisms of MSC-derived EVs actions. Finally, we highlight the modification strategies and diagnosis utilities in order to make advance in this field.

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Evaluation of the neuroprotective effect of taurine in Alzheimer’s disease using functional molecular imaging

Scientific Reports ◽

10.1038/s41598-020-72755-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Se Jong Oh ◽

Hae-June Lee ◽

Ye Ji Jeong ◽

Kyung Rok Nam ◽

Kyung Jun Kang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Imaging ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Treatment Options ◽

Brain Uptake ◽

Positron Emission ◽

Taurine Treatment

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia, but therapeutic treatment options are limited. Taurine has been reported to have neuroprotective properties against dementia, including AD. The present study aimed to investigate the treatment effect of taurine in AD mice by functional molecular imaging. To elucidate glutamate alterations by taurine, taurine was administered to 5xFAD transgenic mice from 2 months of age, known to apear amyloid deposition. Then, we performed glutamate positron emission tomography (PET) imaging studies for three groups (wild-type, AD, and taurine-treated AD, n = 5 in each group). As a result, brain uptake in the taurine-treated AD group was 31–40% higher than that in the AD group (cortex: 40%, p < 0.05; striatum: 32%, p < 0.01; hippocampus: 36%, p < 0.01; thalamus: 31%, p > 0.05) and 3–14% lower than that in the WT group (cortex: 10%, p > 0.05; striatum: 15%, p > 0.05; hippocampus: 14%, p > 0.05; thalamus: 3%, p > 0.05). However, we did not observe differences in Aβ pathology between the taurine-treated AD and AD groups in immunohistochemistry experiments. Our results reveal that although taurine treatment did not completely recover the glutamate system, it significantly increased metabolic glutamate receptor type 5 brain uptake. Therefore, taurine has therapeutic potential against AD.

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A Review on: Analytical Techniques Development and Validation of Drugs Used for Alzheimer’s Disease

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i55a33827 ◽

2021 ◽

pp. 228-243

Author(s):

Sunayana Kesharwani ◽

Parul Mehta

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Liquid Chromatography ◽

Method Development ◽

Neurodegenerative Disorder ◽

Analytical Techniques ◽

Long Term Treatment ◽

Method Development And Validation ◽

Pharmaceutical Industries ◽

Development And Validation

Pharmaceutical analysis plays a very prominent role in quality assurance as well as quality control of bulk drugs and pharmaceutical formulations. Rapid increase in pharmaceutical industries and production of drug in various parts of the world has brought a rise in demand for new analytical techniques in the pharmaceutical industries. As a consequence, analytical method development has become the basic activity of analysis. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory defeat and impairment in behavior, language and visuospatial skills. Donepezil, rivastigmine, galantamine, tacrine and memantine are the US Food and Drug Administration approved oral drugs used in the treatment of AD. These drugs can provide a symptomatic relief but they poorly affect the progression of the disease. Quantization of these drugs in various biological matrices, dosage forms and monitoring them in long-term treatment is essential to titer the dose of these drugs and ensures patient compliance. The main objective of this review mainly focused on spectrophotometric, high-performance liquid chromatography (HPLC), HPTLC and liquid chromatography-mass spectroscopy (LC-MS) which can be used for method development and validation of different Alzheimer’s drugs. The review is a collection of data including various analytical methods used, the different columns used, mobile phase used, flow rate, different detectors and detection wavelength and retention time. This review includes discussion on method development and validation of Alzheimer’s drugs and newly developed compounds which have lesser side effects and are proving more efficient for treatment of Alzheimer’s disease. This review challenges to researches for development of front line drug for Alzheimer’s disease.

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Naturally Inspired Pyrimidines Analogues for Alzheimer’s Disease

Current Neuropharmacology ◽

10.2174/1570159x18666201111110136 ◽

2020 ◽

Vol 19 (2) ◽

pp. 136-151

Author(s):

Shivani Singh ◽

Meenakshi Dhanawat ◽

Sumeet Gupta ◽

Deepak Kumar ◽

Saloni Kakkar ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Multicomponent Reactions ◽

Neurodegenerative Disorder ◽

The Body ◽

New Drugs ◽

Atom Economy ◽

Step Process ◽

One Step ◽

Made In

: Alzheimer’s disease (AD) is a multifarious and developing neurodegenerative disorder. The treatment of AD is still a challenge and availability of drug therapy on the basis of symptoms is not up to the mark. In the context of existence, which is getting worse for the human brain, it is necessary to take care of all critical measures. The disease is caused due to multidirectional pathology of the body, which demands the multi-target-directed ligand (MTDL) approach. This gives hope for new drugs for AD, summarized here in with the pyrimidine based natural product inspired molecule as a lead. The review is sufficient in providing a list of chemical ingredients of the plant to cure AD and screen them against various potential targets of AD. The synthesis of a highly functionalized scaffold in one step in a single pot without isolating the intermediate is a challenging task. In few examples, we have highlighted the importance of this kind of reaction, generally known as multi-component reaction. Multi-component is a widely accepted technique by the drug discovery people due to its high atom economy. It reduces multi-step process to a one-step process, therefore the compounds library can be made in minimum time and cost. This review has highlighted the importance of multicomponent reactions by giving the example of active scaffolds of pyrimidine/fused pyrimidines. This would bring importance to the fast as well as smart synthesis of bio-relevant molecules.

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Drug Repurposing for Alzheimer’s Disease based on Protein-Protein Interaction Network

10.21203/rs.3.rs-398606/v1 ◽

2021 ◽

Author(s):

Negar Sadat Soleimani Zakeri ◽

Saeid Pashazadeh ◽

Habib MotieGhader

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Interactions ◽

Neurodegenerative Disorder ◽

Gentian Violet ◽

Interaction Network ◽

New Drugs ◽

Bipartite Network ◽

Medical Studies ◽

Gene Complexes

Abstract Background: Alzheimer's disease (AD) is known as a critical neurodegenerative disorder. It worsens as symptoms concerning dementia grow severe over the years. Due to the globalization of Alzheimer’s disease, its prevention and treatment is vital. This study proposes a method to extract substantial gene complexes and accomplish an enrichment analysis to introduce the most significant biological procedures. The next step is extracting the drugs related to AD and introduce some new drugs which may be useful for this disease. Results: To this end, protein-protein interactions (PPI) network was utilized to extract five meaningful gene complexes functionally interconnected. The next step was to construct a five bipartite network representing the genes of each group and their target miRNAs. Finally, a complete network including all the genes related to each gene complex group and genes’ target drug was illustrated. medical studies and publications were analyzed thoroughly to introduce AD-related drugs. Conclusions: This analysis proves the accuracy of the proposed method in this study. Then, new drugs were introduced that can be experimentally examined as future work. RALOXIFENE, GENTIAN VIOLET are two new drugs, which have not been introduced as AD-related drugs in previous scientific and medical studies, recommended by the method of this study. These two drugs.

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Loss in efficacy measures of tolfenamic acid in a tau knock-out model: Relevance to Alzheimer’s disease

Experimental Biology and Medicine ◽

10.1177/1535370219871249 ◽

2019 ◽

Vol 244 (13) ◽

pp. 1062-1069

Author(s):

Allison Leso ◽

Syed W Bihaqi ◽

Anwar Masoud ◽

Joanna K Chang ◽

Asma Lahouel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Tolfenamic Acid ◽

New Drugs ◽

Healthy Human ◽

Knock Out ◽

Anti Inflammatory ◽

Diseased State ◽

The Impact

In the healthy human brain, the protein tau serves the essential function of stabilizing microtubules. However, in a diseased state, tau becomes destabilized and aggregates into a pathogenic form that ultimately creates one of the two major hallmarks of Alzheimer’s disease (AD), tau tangles. Multiple neurodegenerative diseases, termed tauopathies, such as Pick’s disease, and progressive supranuclear palsy, are also linked to mutations in tau. While AD does include a second hallmark in the form of amyloid beta (Aβ) plaques, to date all therapeutics aimed at these hallmark features have failed. The nonsteroidal anti-inflammatory drug tolfenamic acid (TA) has been shown to reduce the levels of multiple neurodegenerative endpoints viz amyloid precursor protein (APP), Aβ, tau, phosphorylated tau (p-tau) and improve cognitive function, in various murine models, via a new mechanism that targets specificity protein 1 ( SP1). Sp1 is a zinc-finger transcription factor essential for the regulation of tau and CDK5 genes (among others). The impact of TA on these neurodegenerative endpoints occurred in animal models and systems in which both the tau and the APP genes were present. The experimental model utilized in this paper tested whether the same beneficial outcomes of TA can take place after the removal of endogenous murine tau. We found that the impact of TA, both molecular and behavioral, was no longer significant in the absence of the tau gene. This ability of TA occurred independently of its action on anti-inflammatory targets. Therefore, these findings suggest the essentiality of tau for the novel mechanism of action of TA. Impact statement The number of people suffering from Alzheimer’s disease (AD) is expected to increase exponentially in the coming decades. It is estimated to cost the economy about $200 billion annually. With the failure of standard therapeutic approaches, there is a need to develop new drugs in order to avoid an “epidemic crisis” in the future. We have discovered that tolfenamic acid (TA) lowers the levels of proteins associated with AD, by targeting common transcriptional mechanisms that regulate genes involved in common pathogenic pathways. Here, we investigated whether TA had effects on both the amyloid and tau pathways, or whether it selectively targets one of these pathways which impacted the other. Behavioral and molecular studies revealed that TA loses its AD therapeutic potential when tau gene is removed. This ability of TA occurred independently of its action on anti-inflammatory targets. These findings suggest that tau is essential for the new action of TA.

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A Systematic Review on Donepezil-based Derivatives as Potential Cholinesterase Inhibitors for Alzheimer’s Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666180517094023 ◽

2019 ◽

Vol 26 (30) ◽

pp. 5625-5648 ◽

Cited By ~ 9

Author(s):

Jan Korabecny ◽

Katarina Spilovska ◽

Eva Mezeiova ◽

Ondrej Benek ◽

Radomir Juza ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholinesterase Inhibitors ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Nmda Receptor Antagonist ◽

Amyloid Burden ◽

Ache Inhibitors ◽

Intellectual Capacity ◽

Β Amyloid

: Alzheimer’s Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of β-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.

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