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Bioorganic Chemistry Jun 2024The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular...
The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aβ) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from β,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aβ aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aβ aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10 cm/s. In addition to its Aβ inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aβ induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.
Topics: Alzheimer Disease; Humans; Animals; Mice; Amyloid beta-Peptides; Amides; Protein Aggregates; Structure-Activity Relationship; Molecular Structure; Dose-Response Relationship, Drug; Molecular Docking Simulation; tau Proteins; Neuroprotective Agents; Male
PubMed: 38653149
DOI: 10.1016/j.bioorg.2024.107373 -
Medicine Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.
OBJECTIVE
The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.
METHODS
We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.
RESULTS
All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.
CONCLUSION
ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.
Topics: Humans; Alzheimer Disease; Donepezil; Galantamine; Memantine; Molecular Docking Simulation; Cholinesterase Inhibitors; Rivastigmine
PubMed: 38640313
DOI: 10.1097/MD.0000000000037799 -
Aging Clinical and Experimental Research Apr 2024Although donepezil is a commonly used drug for treating Alzheimer's disease (AD), the mechanisms by which it affects patients' functional brain activity, and thus...
BACKGROUND
Although donepezil is a commonly used drug for treating Alzheimer's disease (AD), the mechanisms by which it affects patients' functional brain activity, and thus modulates clinical symptoms, remain unclear.
METHODS
In the present study, we used resting-state functional magnetic resonance imaging (MRI) and regional homogeneity (ReHo) to investigate the effects of donepezil on local brain activity in AD patients. Resting-state functional MRI data were collected from 32 subjects: 16 healthy controls and 16 AD patients. All 16 AD patients underwent 6 months of donepezil treatment and received two MRI scans (pre- and post-intervention). Analysis of covariance and post hoc analyses were used to compare ReHo differences among the healthy controls, pre-intervention AD patients, and post-intervention AD patients. Pearson correlation analysis was used to examine relationships between ReHo values in differential brain regions and clinical symptoms.
RESULTS
Compared with healthy controls, post-intervention AD patients had reduced ReHo in the orbital part of the inferior frontal gyrus, and pre-intervention AD patients had reduced ReHo in the orbital part of the right inferior frontal gyrus. Pattern recognition models revealed that pre-intervention ReHo values in abnormal brain regions of AD patients were 76% accurate for predicting the efficacy of donepezil on cognitive function and 65% accurate for predicting its efficacy on depressive symptoms.
CONCLUSIONS
These findings deepen our understanding of the brain mechanisms underlying the clinical efficacy of donepezil in AD patients, and provide a novel way to predict its clinical efficacy in such patients.
Topics: Humans; Donepezil; Alzheimer Disease; Prefrontal Cortex; Brain; Cognition
PubMed: 38630202
DOI: 10.1007/s40520-023-02691-6 -
The International Journal of... May 2024Alzheimer's disease (AD) is one of the most challenging and prevalent neurodegenerative disorder globally with a rising prevalence, characterized by progressive...
BACKGROUND
Alzheimer's disease (AD) is one of the most challenging and prevalent neurodegenerative disorder globally with a rising prevalence, characterized by progressive cognitive decline, memory loss, and behavioural changes. Current research aims to determine the nootropic and anti-amnesic effect of Empagliflozin (EMPA) against scopolamine-induced amnesia in rats, by modulating the cholinergic and N-Methyl D-Aspartate (NMDA) receptors.
METHODS
Rats were treated once daily with an EMPA (5 and 10 mg/kg) and donepezil (2.5 mg/kg) for successive 26 days. During the final 13 days of treatment, a daily injection of scopolamine (1 mg/kg) was administered to induce cognitive deficits.
RESULTS
EMPA was found to be significantly reduce escape latency, increase time spent in the target quadrant, and enhanced the number of target zone crossings in the Morris water maze (MWM) test, indicating improved spatial memory. Moreover, EMPA increased the recognition index and the number of spontaneous alternations in the novel object recognition (NOR) and Y-maze tests, respectively, suggesting enhanced memory.
DISCUSSION
Interestingly doses of EMPA (5 mg/kg, 10 mg/kg) exhibited memory-enhancing effects even in the absence of scopolamine-induced impairment. Biochemical analysis revealed that EMPA elevated the levels of glutathione (GSH), a potent antioxidant, while decreasing lipid peroxidation (LPO) activity and increasing catalase (CAT) levels, indicating its antioxidative properties. Interestingly molecular docking studies revealed that EMPA fit perfectly in the active sites of M1 muscarinic acetylcholine (mACh) and NMDA receptors. These results indicated that the nootropic and antiamnesic effect of EMPA is possibly mediated M1 and NMDA receptors and might be a remedy for AD.
PubMed: 38626288
DOI: 10.1080/00207454.2024.2342973 -
Toxicology Research Apr 2024Alzheimer's disease (ad) is a neurological condition that worsens over time and is characterized by the buildup of amyloid (Aβ) plaques in the brain parenchyma....
Ameliorative anti-coagulant, anti-oxidative and anti-ferroptotic activities of nanocurcumin and donepezil on coagulation, oxidation and ferroptosis in Alzheimer's disease.
Alzheimer's disease (ad) is a neurological condition that worsens over time and is characterized by the buildup of amyloid (Aβ) plaques in the brain parenchyma. Neuroprotection and cholinesterase inhibition have been the two primary techniques used in the creation of medications to date. In ad, a novel sort of programmed cell death known as ferroptosis takes place along with iron buildup, lipid peroxidation, and glutathione deficiency. The objective of the current investigation was to examine the neuroprotective and anti-ferroptotic role of nanocurcumin and Donepezil against model of aluminum chloride AlCl and D-galactose induced ad. The experiment was performed on 70 rats divided into (G1: control, G2: NCMN, G3: Donepezil, G4: ad-model, G5: Donepezil co-treatment, G6: NCMN co-treatment and G7: NCMN+Donepezil co-treatment). Hematological parameters and biochemical investigations as oxidative stress, liver function, kidney function, iron profile and plasma fibrinogen were evaluated. Treatment with Nanocurcumin alone or in combination with Donepezil improved oxidative stress, liver functions, and kidney functions, improve iron profile and decreased plasma fibrinogen.
PubMed: 38617712
DOI: 10.1093/toxres/tfae054 -
ACS Omega Apr 2024Alzheimer's disease (AD) is the most common type of dementia, affecting over 50 million people worldwide. Currently, most approved medications for AD inhibit the...
Alzheimer's disease (AD) is the most common type of dementia, affecting over 50 million people worldwide. Currently, most approved medications for AD inhibit the activity of acetylcholinesterase (AChE), but these treatments often come with harmful side effects. There is growing interest in the use of natural compounds for disease prevention, alleviation, and treatment. This trend is driven by the anticipation that these substances may incur fewer side effects than existing medications. This research presents a computational approach combining machine learning with structural modeling to discover compounds from medicinal mushrooms with a high potential to inhibit the activity of AChE. First, we developed a deep neural network capable of rapidly screening a vast number of compounds to indicate their potential to inhibit AChE activity. Subsequently, we applied deep learning models to screen the compounds in the BACMUSHBASE database, which catalogs the bioactive compounds from cultivated and wild mushroom varieties local to Thailand, resulting in the identification of five promising compounds. Next, the five identified compounds underwent molecular docking techniques to calculate the binding energy between the compounds and AChE. This allowed us to refine the selection to two compounds, erinacerin A and hericenone B. Further analysis of the binding energy patterns between these compounds and the target protein revealed that both compounds displayed binding energy profiles similar to the combined characteristics of donepezil and galanthamine, the prescription drugs for AD. We propose that these two compounds, derived from (also known as lion's mane mushroom), are suitable candidates for further research and development into symptom-alleviating AD medications.
PubMed: 38617639
DOI: 10.1021/acsomega.3c10459 -
Pharmaceutical Nanotechnology Apr 2024Dementia associated with Alzheimer's disease (AD) is a neurological disorder. AD is a progressive neurodegenerative condition that predominantly impacts the elderly...
BACKGROUND
Dementia associated with Alzheimer's disease (AD) is a neurological disorder. AD is a progressive neurodegenerative condition that predominantly impacts the elderly population, although it can also manifest in younger people through the impairment of cognitive functions, such as memory, cognition, and behaviour. Donepezil HCl and Memantine HCl are encapsulated in Nanostructured Lipid Carriers (NLCs) to prolong systemic circulation and minimize the systemic side effects.
OBJECTIVE
This work explores the use of data mining tools to optimize the formulation of NLCs comprising of Donepezil HCl and Memantine HCl for transdermal drug delivery. Neuroprotective drugs and excipients are utilized for protecting the nervous system against damage or degeneration.
METHOD
The NLCs were formulated using a high-speed homogenization technique followed by ultrasonication. NLCs were optimized using Box Behnken Design (BBD) in Design Expert Software and artificial neural network (ANN) in IBM SPSS statistics. The independent variables included the ratio of solid lipid to liquid lipid, the percentage of surfactant, and the revolutions per minute (RPM) of the high-speed homogenizer.
RESULTS
The NLCs that were formulated had a mean particle size ranging from 67.0±0.45 to 142.4±0.52nm. Both drugs have a %EE range over 75%, and Zeta potential was determined to be - 26±0.36mV. CryoSEM was used to do the structural study. The permeation study showed the prolonged release of the formulation.
CONCLUSION
The results indicate that NLCs have the potential to be a carrier for transporting medications to deeper layers of the skin and reaching systemic circulation, making them a suitable formulation for the management of Dementia. Both ANN and BBD techniques are effective tools for systematically developing and optimizing NLC formulation.
PubMed: 38616760
DOI: 10.2174/0122117385294969240326052312 -
BMC Chemistry Apr 2024In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and...
Amino-7,8-dihydro-4H-chromenone derivatives as potential inhibitors of acetylcholinesterase and butyrylcholinesterase for Alzheimer's disease management; in vitro and in silico study.
In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the management of Alzheimer's disease (AD). The target compounds were evaluated against AChE and BChE in vitro, and 4k exhibited good potency against BChE (IC = 0.65 ± 0.13 µM) compared with donepezil used as a positive control. Kinetic studies revealed that compound 4k exhibited a competitive-type inhibition with a K value of 0.55 µM. Molecular docking and molecular dynamics simulations further supported the rationality of our design strategy, as 4k showed promising binding interactions with the active sites of BChE. Overall, our findings highlight the potential of amino-7,8-dihydro-4H-chromenone derivatives as promising candidates for developing novel therapeutics targeting cholinesterase in managing AD.
PubMed: 38600537
DOI: 10.1186/s13065-024-01170-x -
Archiv Der Pharmazie Apr 2024A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the...
A series of tacrine-donepezil hybrids were synthesized as potential multifunctional anti-Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine-donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed-type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine-donepezil hybrids also exhibited significant neuroprotection against HO-induced cell death in a differentiated human neuroblastoma (SH-SY5Y) cell line at concentrations close to their IC values on ChEs and showed high to medium blood-brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC-5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH-SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine-donepezil scaffold represents a promising starting point for the development of novel anti-ChE multifunctional agents against AD.
PubMed: 38593283
DOI: 10.1002/ardp.202300575 -
RSC Advances Apr 2024Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily... (Review)
Review
Alzheimer is an irreversible progressive neurodegenerative disease that causes failure of cerebral neurons and disability of the affected person to practice normal daily life activities. There is no concrete evidence to identify the exact reason behind the disease, so several relevant hypotheses emerged, highlighting many possible therapeutic targets, such as acetylcholinesterase, cholinergic receptors, -methyl d-aspartate receptors, phosphodiesterase, amyloid β protein, protein phosphatase 2A, glycogen synthase kinase-3 beta, β-secretase, γ-secretase, α-secretase, serotonergic receptors, glutaminyl cyclase, tumor necrosis factor-α, γ-aminobutyric acid receptors, and mitochondria. All of these targets have been involved in the design of new potential drugs. An extensive number of these drugs have been studied in clinical trials. However, only galantamine, donepezil, and rivastigmine (ChEIs), memantine (NMDA antagonist), and aducanumab and lecanemab (selective anti-Aβ monoclonal antibodies) have been approved for AD treatment. Many drugs failed in the clinical trials to such an extent that questions have been posed about the significance of some of the aforementioned targets. On the contrary, the data of other drugs were promising and shed light on the significance of their targets for the development of new potent anti-alzheimer drugs.
PubMed: 38586442
DOI: 10.1039/d3ra08333k