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Molecules (Basel, Switzerland) Jan 2024Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's...
Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, , , and displayed significant AChE inhibitory activity, with IC values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, (IC = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, (84.08%), (79.30%), and (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that , a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.
Topics: Humans; Monoamine Oxidase; Alzheimer Disease; Monoamine Oxidase Inhibitors; Cyclooxygenase 2; Molecular Docking Simulation; Cholinesterase Inhibitors; Structure-Activity Relationship; Tryptamines; Acetylcholinesterase; Ligands
PubMed: 38276568
DOI: 10.3390/molecules29020490 -
Frontiers in Pharmacology 2023Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer's disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is...
Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer's disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is essential for its safe and rational administration. This study aimed to evaluate the correlation between different ChEIs and TdP/QT prolongation. All ChEIs related TdP/QT prolongation cases were retrieved from the FAERS database using standard MedDRA query (SMQ) from the first quarter of 2004 to the third quarter of 2022. Disproportionality and sensitivity analysis were used to determine the signal of TdP/QT prolongation related to ChEIs. 557 cases of TdP/QT prolongation related to 3 ChEIs were searched by SMQ. The patients were mostly elderly people, with markedly more female than male. The signals of TdP/QT prolongation for ChEIs were detected by disproportionality analysis, and the signal of Donepezil was the strongest. The sensitivity analysis results indicate a robust and stable correlation between these signals with ChEIs. TdP/QT prolongation usually occurs within 1 month after taking ChEIs. The drug with the highest frequency of combination with donepezil and galantamine is citalopram, and the drug with the highest frequency of combination with rivastigmine is atorvastatin. The signals of TdP/QT prolongation related to ChEIs were strong and stable. It is necessary to be vigilant about the TdP/QT prolongation of various ChEIs, especially in elderly women, the initial stage after taking ChEIs, and when ChEIs combining with drugs that could prolong the QT interval.
PubMed: 38273821
DOI: 10.3389/fphar.2023.1343650 -
Plants (Basel, Switzerland) Jan 2024Lignan phytomolecules demonstrate promising anti-Alzheimer activity by alleviating dementia and preserving nerve cells. The purpose of this work is to characterize the...
Furofuranoid-Type Lignans and Related Phenolics from (Salisb.) Nees with Promising Anticholinesterase and Anti-Ageing Properties: A Study Supported by Molecular Modelling.
Lignan phytomolecules demonstrate promising anti-Alzheimer activity by alleviating dementia and preserving nerve cells. The purpose of this work is to characterize the lignans of and explore their potential anti-acetylcholinesterase and anti-ageing effects. Phytochemical investigation of aerial parts afforded a new furofuranoid-type lignan (), four known structural analogues, namely pinoresinol (), epipinoresinol (), phillyrin (), and pinoresinol 4---d-glucoside (), in addition to -methoxy--methyl cinnamate () and 1H-indole-3-carboxaldehyde (). The structures were established from thorough spectroscopic analyses and comparisons with the literature. Assessment of the anticholinesterase activity of the lignans - displayed noticeable enzyme inhibition of (IC = 85.03 ± 4.26 nM) and (64.47 ± 2.75 nM) but lower activity of compounds - as compared to the reference drug donepezil. These findings were further emphasized by molecular docking of and with acetylcholinesterase (AChE). Rapid overlay chemical similarity (ROCS) and structure-activity relationships (SAR) analysis highlighted and rationalized the anti-AD capability of these compounds. Telomerase activation testing of the same isolates revealed 1.64-, 1.66-, and 1.72-fold activations in cells treated with compounds , , and , respectively, compared to untreated cells. Our findings may pave the way for further investigations into the development of anti-Alzheimer and/or anti-ageing drugs from furofuranoid-type lignans.
PubMed: 38256704
DOI: 10.3390/plants13020150 -
Biomedicines Dec 2023Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive... (Review)
Review
Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions. Both models show long-lasting and generalized pain and female-predominant sex differences after gonadectomy. Like many other neuropathic pain models, ICGP and IPGP were abolished in lysophosphatidic acid receptor 1 (LPAR) knock-out mice or by LPAR antagonist treatments, although deciding the clinical importance of this mechanism depends on waiting for the development of a clinically available LPAR antagonist. On the other hand, the nonsteroidal anti-inflammatory drug diclofenac with morphine did not suppress hyperalgesia in these models, and this is consistent with the clinical findings. Pharmacological studies suggest that the lack of morphine analgesia is associated with opioid tolerance upon the stress-induced release of endorphins and subsequent counterbalance through anti-opioid NMDA receptor mechanisms. Regarding pharmacotherapy, hyperalgesia in both models was suppressed by pregabalin and duloxetine, which have been approved for FM treatment in clinic. Notably, repeated treatments with mirtazapine, an α2 adrenergic receptor antagonist-type antidepressant, and donepezil, a drug for treating Alzheimer's disease, showed potent therapeutic actions in these models. However, the pharmacotherapeutic treatment should be carried out 3 months after stress, which is stated in the FM guideline, and many preclinical studies, such as those analyzing molecular and cellular mechanisms, as well as additional evidence using different animal models, are required. Thus, the ICGP and IPGP models have the potential to help discover and characterize new therapeutic medicines that might be used for the radical treatment of FM, although there are several limitations to be overcome.
PubMed: 38255163
DOI: 10.3390/biomedicines12010056 -
Scientific Reports Jan 2024Alzheimer's disease (AD) is a multifaceted neurodegenerative condition. The pathogenesis of AD is highly intricate and the disease is apparent in the aged...
Alzheimer's disease (AD) is a multifaceted neurodegenerative condition. The pathogenesis of AD is highly intricate and the disease is apparent in the aged population ~ 50-70 years old. Even after > 100 years of research, the root origin of AD and its pathogenesis is unclear, complex and multifaceted. Herein, we have designed and synthesized 9 novel molecules with three different heterocyclic scaffolds namely pyrrolidone-2-one, quinoline & indoline-2-one to imitate and explore the novel chemical space around donepezil. The synthesized molecules were evaluated for their potential as anti-Alzheimer's agents through in-vitro and in-vivo studies in appropriate animal models. To further understand their interaction with acetylcholinesterase enzyme (AChE), extra-precision docking, and molecular dynamics simulation studies were carried out. As the number of compounds was limited to thoroughly explore the structure-activity relationship, atom-based 3D-quantitative structure-activity relationships (QSAR) studies were carried out to get more insights. All the designed compounds were found to inhibit AChE with IC in the micromolar range. From pyrrolidone-2-one series, 6-chloro-N-(1-(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)pyridine-3-sulfonamide (9), 2-(1-benzylpiperidin-4-yl)-6,7-dimethoxy-4-(4-methoxyphenyl)quinoline (18) from quinoline series and N-(1-benzylpiperidin-4-yl)-2-(2-oxoindolin-3-yl)acetamide (23) from indolin-2-one series inhibited AChE with an IC value of 0.01 µM. Based on other biochemical studies like lipid peroxidation, reduced glutathione, superoxide dismutase, catalase, nitrite, and behavioural studies (Morris water maze), compound 9 was found to be a potent AChE inhibitor which can be further explored as a lead molecule to design more potent and effective anti-Alzheimer's agents.
Topics: Animals; Donepezil; Acetylcholinesterase; Cholinesterase Inhibitors; Alzheimer Disease; Structure-Activity Relationship; Quantitative Structure-Activity Relationship; Pyrrolidinones; Quinolines; Molecular Docking Simulation; Pyridines; Sulfonamides
PubMed: 38242995
DOI: 10.1038/s41598-024-51713-4 -
IScience Jan 2024In an innovative experiment, we detected ultraweak photon emission (UPE) from the hippocampus of male rat brains and found significant correlations between Alzheimer's...
In an innovative experiment, we detected ultraweak photon emission (UPE) from the hippocampus of male rat brains and found significant correlations between Alzheimer's disease (AD), memory decline, oxidative stress, and UPE intensity. These findings may open up novel methods for screening, detecting, diagnosing, and classifying neurodegenerative diseases, particularly AD. The study suggests that UPE from the brain's neural tissue can serve as a valuable indicator. It also proposes the development of a minimally invasive brain-computer interface (BCI) photonic chip for monitoring and diagnosing AD, offering high spatiotemporal resolution of brain activity. The study used a rodent model of sporadic AD, demonstrating that STZ-induced sAD resulted in increased hippocampal UPE, which was associated with oxidative stress. Treatment with donepezil reduced UPE and improved oxidative stress. These findings support the potential utility of UPE as a screening and diagnostic tool for AD and other neurodegenerative diseases.
PubMed: 38235338
DOI: 10.1016/j.isci.2023.108744 -
Cureus Dec 2023Dementia is a debilitating neurological condition that is characterized by persistent cognitive decline. It is a global health challenge, with a rapidly increasing... (Review)
Review
Dementia is a debilitating neurological condition that is characterized by persistent cognitive decline. It is a global health challenge, with a rapidly increasing prevalence due to an increasing aging population. Although definitive diagnosis of various conditions of dementia is only possible by autopsy, clinical diagnosis can be performed by a specialist. The diagnostic process has evolved with recent breakthroughs in diagnostic tools, such as advanced imaging techniques and biomarkers. These tools facilitate early and accurate identification of the condition. Early diagnosis is vital, as it enables timely interventions to improve the quality of life for affected individuals. Treatment strategies for dementia encompass both pharmacological and non-pharmacological approaches. Non-pharmacological treatments include cognitive training and lifestyle modifications. Among pharmacological treatments, acetyl-cholinesterase inhibitors including donepezil, rivastigmine, and galantamine can be used in various doses based on the severity of the disease. Apart from these, N-methyl-D-aspartate receptor antagonists such as memantine can also be used. Furthermore, personalized treatments have also gained significant attention in dementia treatment. Interdisciplinary care, involving healthcare professionals, social workers, and support networks, is crucial for comprehensive and holistic dementia management.
PubMed: 38222245
DOI: 10.7759/cureus.50522 -
BMC Public Health Jan 2024The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014,... (Observational Study)
Observational Study
Changes in dementia treatment patterns associated with changes in the National Policy in South Korea among patients with newly diagnosed Alzheimer's disease between 2011 and 2017: results from the multicenter, retrospective CAPTAIN study.
BACKGROUND
The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function training program and home nursing service. This study aimed to investigate changes in treatment patterns for Alzheimer's disease (AD) between July 2011 and June 2017 which spanned the 2014 revision.
METHODS
This multicenter, retrospective, observational study of patients with newly diagnosed AD analyzed electronic medical records from 17 general hospitals across South Korea. Based on their time of AD diagnosis, subjects were categorized into Cohort 1 (1 July 2011 to 30 June 2014) and Cohort 2 (1 July 2014 to 30 June 2017).
RESULTS
Subjects (N=3,997) divided into Cohorts 1 (n=1,998) and 2 (n=1,999), were mostly female (66.4%) with a mean age of 84.4 years. Cohort 1 subjects were significantly older (P<0.0001) and had a lower number of comorbidities (P=0.002) compared with Cohort 2. Mean Mini-Mental State Examination (MMSE) scores in Cohorts 1 and 2 at the time of AD diagnosis or start of initial treatment were 16.9 and 17.1, respectively (P=0.2790). At 1 year, mean MMSE scores in Cohorts 1 and 2 increased to 17.9 and 17.4, respectively (P=0.1524). Donepezil was the most frequently administered medication overall (75.0%), with comparable rates between cohorts. Rates of medication persistence were ≥98% for acetylcholinesterase inhibitor or memantine therapy. Discontinuation and switch treatment rates were significantly lower (49.7% vs. 58.0%; P<0.0001), and mean duration of initial treatment significantly longer, in Cohort 2 vs. 1 (349.3 vs. 300.2 days; P<0.0001).
CONCLUSIONS
Comparison of cohorts before and after revision of the national LTCI system for dementia patients found no significant difference in mean MMSE scores at the time of AD diagnosis or start of initial treatment. The reduction in the proportion of patients who discontinued or changed their initial treatment, and the significant increase in mean duration of treatment, were observed following revision of the LTCI policy which enabled increased patient access to long-term care.
Topics: Humans; Female; Aged, 80 and over; Male; Alzheimer Disease; Retrospective Studies; Acetylcholinesterase; Donepezil; Cholinesterase Inhibitors
PubMed: 38216922
DOI: 10.1186/s12889-024-17671-2 -
Molecules (Basel, Switzerland) Dec 2023A facial and efficient method for the screening of acetylcholinesterase (AChE) inhibitors by capillary electrophoresis was developed. Based on the specific affinity of...
A facial and efficient method for the screening of acetylcholinesterase (AChE) inhibitors by capillary electrophoresis was developed. Based on the specific affinity of concanavalin A (Con A) for binding to the glycosyl group of AChE, enzyme molecules were oriented-immobilized on the surface of gold nanoparticles (AuNPs@Con A@AChE). Then, these modified nanoparticles were bounded to the capillary inlet (about 1.0 cm) by electrostatic self-assembly to obtain the oriented-immobilized enzyme microreactor (OIMER). Compared to an IMER with a free enzyme, the peak area of the product obtained by the OIMER increased by 52.6%. The Michaelis-Menten constant () was as low as (0.061 ± 0.003) mmol/L. The method exhibits good repeatability with a relative standard deviation (RSD) of 1.3% for 100 consecutive runs. The system was successfully applied to detect the IC values of donepezil and four components from Chinese medicinal plants. This work demonstrates the potential of this method as a low cost, simple, and accurate screening method for other enzyme inhibitors.
Topics: Cholinesterase Inhibitors; Enzymes, Immobilized; Acetylcholinesterase; Gold; Metal Nanoparticles; Electrophoresis, Capillary; Concanavalin A
PubMed: 38202701
DOI: 10.3390/molecules29010118 -
Journal of Medicinal Chemistry Jan 2024Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT emerged as a promising target for AD treatment; thus,...
Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT emerged as a promising target for AD treatment; thus, here a new series of 5-HTR ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HTR affinity and selectivity over 5-HTR (-), 5-HTR ( and ), and 5-HTR (). Compound displayed high selectivity for 5-HTR over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.
Topics: Rats; Animals; Alzheimer Disease; Serotonin; Selenium; Rats, Wistar; Neuroprotection; Antioxidants; Receptors, Serotonin; Neuroprotective Agents
PubMed: 38190615
DOI: 10.1021/acs.jmedchem.3c02148