scholarly journals Small-Molecule Inhibitors of GSK-3: Structural Insights and Their Application to Alzheimer's Disease Models

2012 ◽  
Vol 2012 ◽  
pp. 1-32 ◽  
Author(s):  
Thomas Kramer ◽  
Boris Schmidt ◽  
Fabio Lo Monte
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Glycogen Synthase ◽  
World Health ◽  
Neuroprotective Effects ◽  
Cellular Processes ◽  
The Usa ◽  
Health Organization

The world health organization (WHO) estimated that 18 million people are struck by Alzheimer's disease (AD). The USA, France, Germany, and other countries launched major programmes targeting the identification of risk factors, the improvement of caretaking, and fundamental research aiming to postpone the onset of AD. The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of several diseases including diabetes mellitus, cancer, and AD. Inhibition of GSK-3 leads to neuroprotective effects, decreasedβ-amyloid production, and a reduction in tau hyperphosphorylation, which are all associated with AD. Various classes of small molecule GSK-3 inhibitors have been published in patents and original publications. Herein, we present a comprehensive summary of small molecules reported to interact with GSK-3. We illustrate the interactions of the inhibitors with the active site. Furthermore, we refer to the biological characterisation in terms of activity and selectivity for GSK-3, elucidatein vivostudies and pre-/clinical trials.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

Neuroprotective effects of bergenin in Alzheimer’s disease: Investigation through molecular docking, in vitro and in vivo studies

2019 ◽  
Vol 356 ◽  
pp. 18-40 ◽  
Author(s):  
Priyal Barai ◽  
Nisith Raval ◽  
Sanjeev Acharya ◽  
Ankit Borisa ◽  
Hardik Bhatt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
In Vivo Studies ◽  
Neuroprotective Effects

scholarly journals Anti-Inflammatory Activity of A Polyphenolic Extract from Arabidopsis thaliana in In Vitro and In Vivo Models of Alzheimer’s Disease

2019 ◽  
Vol 20 (3) ◽  
pp. 708 ◽  
Author(s):  
Roberto Mattioli ◽  
Antonio Francioso ◽  
Maria d’Erme ◽  
Maurizio Trovato ◽  
Patrizia Mancini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Arabidopsis Thaliana ◽  
Heme Oxygenase 1 ◽  
Neuroprotective Effects ◽  
In Vivo Models ◽  
Polyphenolic Extract ◽  
Anti Inflammatory ◽  
The Impact

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25–35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1–42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases.

scholarly journals Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

2020 ◽  
Vol 2020 ◽  
pp. 1-27 ◽  
Author(s):  
Samuele Maramai ◽  
Mohamed Benchekroun ◽  
Moustafa T. Gabr ◽  
Samir Yahiaoui
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Event ◽  
Neuroprotective Effects ◽  
New Agents ◽  
Major Health ◽  
New Treatment ◽  
Neuronal Functions

Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

An Estrogen Replacement Therapy Containing Nine Synthetic Plant-Based Conjugated Estrogens Promotes Neuronal Survival

2003 ◽  
Vol 228 (7) ◽  
pp. 823-835 ◽  
Author(s):  
Lixia Zhao ◽  
Shuhua Chen ◽  
Roberta D. Brinton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Replacement Therapy ◽  
Estrogen Replacement Therapy ◽  
Neuronal Survival ◽  
Estrogen Replacement ◽  
Neuroprotective Effects ◽  
Conjugated Estrogens ◽  
Neuroprotective Efficacy

Epidemiological data from retrospective and case–control studies have indicated that estrogen replacement therapy can decrease the risk of developing Alzheimer’s disease. In addition, estrogen replacement therapy has been found to promote neuronal survival both in vivo and in vitro. We have shown that conjugated equine estrogens (CEE), containing 238 different molecules composed of estrogens, progestins, and androgens, exerted neurotrophic and neuroprotective effects in cultured neurons. In the current study, we sought to determine whether a steroidal formulation of nine synthetic conjugated estrogens (SCE) chemically derived from soybean and yam extracts is as effective as the complex multisteroidal formulation of CEE. Analyses of the neuroprotective efficacy indicate that SCE exhibited significant neuroprotection against beta amyloid, hydrogen peroxide, and glutamate-induced toxicity in cultured hippocampal neurons. Indices of neuroprotection included an increase in neuronal survival, a decrease in neurotoxin-induced lactate dehydrogenase release, and a reduction in neurotoxin-induced apoptotic cell death. Furthermore, SCE was found to attenuate excitotoxic glutamate-induced [Ca2+]i rise. Quantitative analyses indicate that the neuroprotective efficacy of SCE was comparable to that of the multisteroidal CEE formulation. Data derived from these investigations predict that SCE could exert neuroprotective effects comparable to CEE in vivo and therefore could reduce the risk of Alzheimer’s disease in postmenopausal women.

P4-164: Aβ oligomers as tractable drug targets in Alzheimer's disease: in vivo proof of concept for the oligomer-binding small-molecule therapeutic candidate cbb68

2015 ◽  
Vol 11 (7S_Part_18) ◽  
pp. P841-P842
Author(s):  
Armand W.J.W. Tepper ◽  
Elizabeth C. de Boer ◽  
Emily Hoogveld ◽  
Joost D.J. Vis ◽  
Ivar C. Schut ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Drug Targets ◽  
Proof Of Concept ◽  
Aβ Oligomers

Machine Learning, Molecular Modeling and Qsar Studies of Natural Products against Alzheimer’s Disease

2021 ◽  
Vol 28 ◽  
Author(s):  
Érika Paiva de Moura ◽  
Natan Dias Fernandes ◽  
Alex France Messias Monteiro ◽  
Herbert Igor Rodrigues de Medeiros ◽  
Marcus Tullius Scotti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Neurodegenerative Disorder ◽  
Quantitative Structure Activity Relationship ◽  
World Health ◽  
Qsar Studies ◽  
Structure Activity ◽  
Gradual Loss ◽  
Health Organization

Background: Alzheimer's disease (AD) is a very common neurodegenerative disorder in individuals over 65 years of age, however, younger individuals can also be affected due to early brain damage. Introduction: The general symptoms of this disease include progressive loss of memory, changes in behavior, deterioration of thinking, and gradual loss of ability to perform daily activities. According to the World Health Organization, dementia has affected more than 50 million people worldwide, and it is estimated that there are 10 million new cases per year, of which 70% are due to AD. Methods: This paper reported a review of scientific articles available on the internet, which discussed in silico analyzes, such as molecular docking, molecular dynamics, and quantitative structure-activity relationship (QSAR) of different classes of natural products and their derivatives published from 2016 onwards. In addition, this work reports the potential of fermented papaya preparation against oxidative stress in AD. Results: With this research, it is expected that it will highlight the most recent studies about AD, the computational analysis methods used in proposing new bioactive and their possible molecular targets, and finally, the molecules or classes of natural products involved in each study. Conclusion: Thus, studies like this can orientate new works against neurodegenerative diseases, especially AD.

scholarly journals Acetylcholinesterase Inhibitory Potential of Various Sesquiterpene Analogues for Alzheimer’s Disease Therapy

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 350
Author(s):  
Ashwani Arya ◽  
Rubal Chahal ◽  
Rekha Rao ◽  
Md. Habibur Rahman ◽  
Deepak Kaushik ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activities ◽  
Structural Diversity ◽  
Time Frame ◽  
World Health ◽  
Cholinergic Transmission ◽  
Disease Therapy ◽  
Inhibitory Potential ◽  
Health Organization

Alzheimer’s disease (AD) is a gradually growing irreversible illness of the brain that almost affects every fifth person (aged > 80 years) in the world. World Health Organization (WHO) also revealed that the prevalence of this disease will enhance (upto double) significantly upto 2030. The poor cholinergic transmission at the synapse is considered to be one of the main reasons behind the progression and occurrence of this disorder. Natural inhibitors of acetylcholine (ACh) such as galanthamine and rivastigmine are used commercially in the treatmentof AD. The biomolecules such assesquiterpenes, possess a great structural diversity and are responsible for a plethora of pharmacological properties. The potential of various sesquiterpenes as anticholinesterase has been reviewed in this article. For this purpose, the various databases, mainly PubMed, Scopus, and Web of Science were investigatedwith different keywords such as “sesquiterpenes+acetylcholinesterase” and “sesquiterpenes+cholinesterase+inhibitors” in the surveyed time frame (2010–2020). A vast literature was evident in the last decade, which affirms the potential of various sesquiterpenes in the improvement of cholinergic transmission by inhibiting the AChE. After data analysis, it was found that 12 compounds out of a total of 58 sesquiterpenes were reported to possess IC50 < 9μM and can be considered as potential candidates for the improvement of learning and memory. Sesquiterpene is an important category of terpenoids, found to possess a large spectrum of biological activities. The outcome of the review clearly states that sesquiterpenes (such as amberboin, lipidiol,etc) from herbs could offer fresh, functional compounds for possible prevention and treatment of AD.

Pakistan

2019 ◽  
pp. 61-78 ◽  
Author(s):  
Muhammad Nasar Sayeed Khan ◽  
Muhammad Iqbal Afridi ◽  
Afzel Javed
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Life Expectancy ◽  
Memory Loss ◽  
Developed Countries ◽  
World Health ◽  
Average Life Expectancy ◽  
People With Dementia ◽  
Health Organization ◽  
Number Of Individuals

Pakistan is one of the largest and most populated nations of South Asia and ranked sixth among the most crowded countries in the world, with a population exceeding 196 million. Because of a lack of research and the cultural setting, it is exceptionally hard to obtain an exact number of individuals suffering from dementia. However, the extrapolated prevalence of people with dementia in Pakistan is around 200,000. Compared to developed countries, only 4.2% of the Pakistani population are aged above 65 years, possibly due to an average life expectancy of 66 years for both genders . Although no specific data on elderly people with dementia in Pakistan are available, it is estimated that 8–10% of the general population aged above 65 years suffer from chronic memory loss. According to the latest 2014 World Health Organization data, Alzheimer’s disease/dementia-related deaths in Pakistan reached a total of 1776 or 0.16% of total deaths. Pakistan currently has the largest generation of young people ever recorded in its history, who will be at risk for dementia and Alzheimer’s disease by 2050, at which time, life expectancy would be expected to continue rising. Thus, the economic burden of treating patients with Alzheimer’s disease and other types of dementia will increase considerably.

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