scholarly journals Multi-target Natural and Nature-Inspired Compounds against Neurodegeneration: A Focus on Dual Cholinesterase and Phosphodiesterase Inhibitors

2021 ◽  
Vol 11 (11) ◽  
pp. 5044
Author(s):  
Giovanni Ribaudo ◽  
Maurizio Memo ◽  
Alessandra Gianoncelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phosphodiesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Brain Regions ◽  
Complex Nature ◽  
Promising Alternative ◽  
Biochemical Mechanisms ◽  
Underlying Mechanisms

Alzheimer’s disease is a memory-related neurodegenerative condition leading to cognitive impairment. Cholinergic deficit, together with other underlying mechanisms, leads the to onset and progression of the disease. Consequently, acetylcholinesterase inhibitors are used for the symptomatic treatment of dementia, even if limited efficacy is observed. More recently, some specific phosphodiesterase isoforms emerged as promising, alternative targets for developing inhibitors to contrast neurodegeneration. Phosphodiesterase isoforms 4,5 and 9 were found to be expressed in brain regions that are relevant for cognition. Given the complex nature of Alzheimer’s disease and the combination of involved biochemical mechanisms, the development of polypharmacological agents acting on more than one pathway is desirable. This review provides an overview of recent reports focused on natural and Nature-inspired small molecules, or plant extracts, acting as dual cholinesterase and phosphodiesterase inhibitors. In the context of the multi-target directed ligand approach, such molecules would pave the way for the development of novel agents against neurodegeneration. More precisely, according to the literature data, xanthines, other alkaloids, flavonoids, coumarins and polyphenolic acids represent promising scaffolds for future optimization.

2',6'-dihydroxy-4'-methoxy dihydrochalcone improves the cognitive impairment of Alzheimer's disease: a structure-activity relationship study

2021 ◽  
Vol 21 ◽  
Author(s):  
Ana E. Gonçalves ◽  
Ângela Malheiros ◽  
Camila A. Cazarin ◽  
Lara de França ◽  
David L. Palomino-Salcedo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Learning And Memory ◽  
Acetylcholinesterase Inhibitors ◽  
Inhibitory Avoidance ◽  
Symptomatic Treatment ◽  
Memory Test ◽  
Object Recognition Test ◽  
Docking Simulations ◽  
The Brain

Background: Chalcones and dihydrochalcones present potent inhibition of acetylcholinesterase, which is currently considered the most efficient approach for symptomatic treatment of Alzheimer’s disease. Objective: The present study aimed to explore the potential benefits of 2',6'-dihydroxy-4'-methoxy dihydrochalcone on the cognitive deficits of animals submitted to the streptozotocin-induced Alzheimer's model, as well as to evaluate the possible mechanisms of action. Methods: Learning and memory functions of different groups of animals were submitted to the streptozotocin-induced Alzheimer's model (STZ 2.5 mg/mL, i.c.v.) and subsequently treated with 2',6'-dihydroxy-4'-methoxy dihydrochalcone (DHMDC) administered at doses 5, 15, and 30 mg/kg (p.o.), rivastigmine (0,6 mg/kg, i.p.) and vehicle were evaluated in aversive memory test (inhibitory avoidance test) and spatial memory test (object recognition test). Molecular docking simulations were performed to predict the binding mode of DHMDC at the peripheral site of AChE to analyze noncovalent enzyme-ligand interactions. DFT calculations were carried out to study well-known acetylcholinesterase inhibitors and DHMDC. Results: DHMDC markedly increased the learning and memory of mice. STZ caused a significant decline of spatial and aversive memories in mice, attenuated by DHMDC (15 and 30 mg/kg). Furthermore, STZ conspicuously increased lipid peroxidation and compromised the antioxidant levels in mice brains. DHMDC pretreatment significantly increased GSH activity and other oxidative stress markers and decreased TBARS levels in the brain of STZ administered mice. AChE activity was significantly decreased by DHMDC in the brain of mice. Conclusion: The results together point that DHMDC may be a useful drug in the management of dementia.

scholarly journals New Acetylcholinesterase Inhibitors for Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Mona Mehta ◽  
Abdu Adem ◽  
Marwan Sabbagh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Cholinesterase Inhibitors ◽  
Treatment Approach ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Symptomatic Improvement ◽  
Ache Inhibition ◽  
Different Types

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

scholarly journals Emetine and Indirubin- 3- monoxime interaction with human brain acetylcholinesterase: A computational and statistical analysis

2022 ◽  
Vol 67 (4) ◽  
pp. 106-114
Author(s):  
Syed Sayeed Ahmad ◽  
Haroon Khan ◽  
Mohammad Khalid ◽  
Abdulraheem SA Almalki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Binding Energy ◽  
Human Brain ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Docking Studies ◽  
Coefficient Of Determination ◽  
Intermolecular Energy ◽  
Brain Acetylcholinesterase

Alzheimer's disease is a chronic neurodegenerative ailment and the most familiar type of dementia in the older population with no effective cure to date. It is characterized by a decrease in memory, associated with the mutilation of cholinergic neurotransmission. Presently, acetylcholinesterase inhibitors have emerged as the most endorsed pharmacological medications for the symptomatic treatment of mild to moderate Alzheimer's disease. This study aimed to research the molecular enzymatic inhibition of human brain acetylcholinesterase by a natural compound emetine and I3M. Molecular docking studies were used to identify superior interaction between enzyme acetylcholinesterase and ligands. Furthermore, the docked acetylcholinesterase-emetine complex was validated statistically using an analysis of variance in all tested conformers. In this interaction, H-bond, hydrophobic interaction, pi-pi, and Cation-pi interactions played a vital function in predicting the accurate conformation of the ligand that binds with the active site of acetylcholinesterase. The conformer with the lowest free energy of binding was further analyzed. The binding energy for acetylcholinesterase complex with emetine and I3M was -9.72kcal/mol and -7.09kcal/mol, respectively. In the current study, the prediction was studied to establish a relationship between binding energy and intermolecular energy (coefficient of determination [R2 linear = 0.999), and intermolecular energy and Van der wall forces (R2 linear = 0.994). These results would be useful in gaining structural insight for designing novel lead compounds against acetylcholinesterase for the effective management of Alzheimer's disease.

Potent Acetylcholinesterase Inhibitors: Potential Drugs for Alzheimer’s Disease

2020 ◽  
Vol 20 (8) ◽  
pp. 703-715 ◽  
Author(s):  
Hulya Akıncıoğlu ◽  
İlhami Gülçin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Acetylcholinesterase Inhibitors ◽  
Symptomatic Treatment ◽  
Work Related ◽  
Β Amyloid ◽  
Hydrolysis Of ◽  
Neurotransmitter Substance

: Alzheimer’s disease (AD) is one of the cognitive or memory-related impairments occurring with advancing age. Since its exact mechanism is not known, the full therapy has still not been found. Acetylcholinesterase (AChE) has been reported to be a viable therapeutic target for the treatment of AD and other dementias. To this end, acetylcholinesterase inhibitors (AChEIs) are commonly used. AChE is a member of the hydrolase enzyme family. A hydrolase is an enzyme that catalyzes the hydrolysis of a chemical bond. AChE is useful for the development of novel and mechanism-based inhibitors. It has a role in the breakdown of acetylcholine (ACh) neurotransmitters, such as acetylcholinemediated neurotransmission. AChEIs are the most effective approaches to treat AD. AChE hydrolyzes ACh to acetate and choline, as an important neurotransmitter substance. Recently, Gülçin and his group explored new AChEIs. The most suggested mechanism for AD is the deficiency of ACh, which is an important neurotransmitter. In this regard, AChEIs are commonly used for the symptomatic treatment of AD. They act in different ways, such as by inhibiting AChE, protecting cells from free radical toxicity and β-amyloid-induced injury or inhibiting the release of cytokines from microglia and monocytes. This review focuses on the role of AChEIs in AD using commonly available drugs. Also, the aim of this review is to research and discuss the role of AChEIs in AD using commonly available drugs. Therefore, in our review, related topics like AD and AChEIs are highlighted. Also, the latest work related to AChEIs is compiled. In recent research studies, novel natural and synthetic AChEIs, used for AD, are quite noteworthy. These studies can be very promising in detecting potent drugs against AD.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

Spirocyclohexadienones as an Uncommon Scaffold for Acetylcholinesterase Inhibitory Activity

2019 ◽  
Vol 15 (4) ◽  
pp. 373-382 ◽  
Author(s):  
Ralph C. Gomes ◽  
Renata P. Sakata ◽  
Wanda P. Almeida ◽  
Fernando Coelho
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Aging ◽  
Acetylcholinesterase Inhibitors ◽  
Acetylcholinesterase Activity ◽  
Docking Study ◽  
Biological Properties ◽  
Ache Inhibitor ◽  
Molecular Docking Study

Background: The most important cause of dementia affecting elderly people is the Alzheimer’s disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. Methods: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. Results: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). Conclusion: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.

Old Drugs with New Tricks; Paradigm in Drug Development Pipeline for Alzheimer’s Disease

2020 ◽  
Vol 20 ◽  
Author(s):  
Tanay Dalvi ◽  
Bhaskar Dewangan ◽  
Rudradip Das ◽  
Jyoti Rani ◽  
Suchita Dattatray Shinde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Development ◽  
Molecular Targets ◽  
Drug Repurposing ◽  
Phase Iii ◽  
Complex Nature ◽  
New Drug ◽  
Development Pipeline ◽  
Old Drugs

: The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.

Formononetin Ameliorates Cognitive Disorder via PGC-1α Pathway in Neuroinflammation Conditions in High-Fat Diet-Induced Mice

2019 ◽  
Vol 18 (7) ◽  
pp. 566-577 ◽  
Author(s):  
Xinxin Fu ◽  
Tingting Qin ◽  
Jiayu Yu ◽  
Jie Jiao ◽  
Zhanqiang Ma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Fat Diet ◽  
Trifolium Pratense ◽  
Amyloid Β ◽  
Cognitive Disorder ◽  
Mechanism Study ◽  
High Fat ◽  
Neuroprotective Effects ◽  
Underlying Mechanisms

Background: Alzheimer’s disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer’s disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-β generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer’s disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer’s disease with Formononetin. Objective: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms. Methods: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg). Results: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1β and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-κB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice. Conclusion: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.

Sign in / Sign up

Export Citation Format

Share Document