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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 -
Geniposide and Harpagoside Functionalized Cerium Oxide Nanoparticles as a Potential Neuroprotective.International Journal of Molecular... Apr 2024Alzheimer's disease is associated with protein aggregation, oxidative stress, and the role of acetylcholinesterase in the pathology of the disease. Previous...
Alzheimer's disease is associated with protein aggregation, oxidative stress, and the role of acetylcholinesterase in the pathology of the disease. Previous investigations have demonstrated that geniposide and harpagoside protect the brain neurons, and cerium nanoparticles (CeO NPs) have potent redox and antioxidant properties. Thus, the effect of nanoparticles of Ce NPs and geniposide and harpagoside (GH/CeO NPs) on ameliorating AD pathogenesis was established on AlCl-induced AD in mice and an aggregation proteins test in vitro. Findings of spectroscopy analysis have revealed that GH/CeO NPs are highly stable, nano-size, spherical in shape, amorphous nature, and a total encapsulation of GH in cerium. Treatments with CeO NPs, GH/CeO NPs, and donepezil used as positive control inhibit fibril formation and protein aggregation, protect structural modifications in the BSA-ribose system, have the ability to counteract Tau protein aggregation and amyloid-β1-42 aggregation under fibrillation condition, and are able to inhibit AChE and BuChE. While the GH/CeO NPs, treatment in AD induced by AlCl inhibited amyloid-β1-42, substantially enhanced the memory, the cognition coordination of movement in part AD pathogenesis may be alleviated through reducing amyloidogenic pathway and AChE and BuChE activities. The findings of this work provide important comprehension of the chemoprotective activities of iridoids combined with nanoparticles. This could be useful in the development of new therapeutic methods for the treatment of neurodegenerative diseases.
Topics: Cerium; Iridoids; Animals; Neuroprotective Agents; Mice; Alzheimer Disease; Acetylcholinesterase; Amyloid beta-Peptides; Male; Nanoparticles; Metal Nanoparticles; Disease Models, Animal
PubMed: 38673848
DOI: 10.3390/ijms25084262 -
International Journal of Molecular... Nov 2023This study investigated the neuroprotective effects of leaves and stems (DMLS) water extract on scopolamine (SCO)-induced memory impairment in mice. First, we conducted...
This study investigated the neuroprotective effects of leaves and stems (DMLS) water extract on scopolamine (SCO)-induced memory impairment in mice. First, we conducted experiments to determine the protective effect of DMLS on neuronal cells. Treatment with DMLS showed a significant protective effect against neurotoxicity induced by Aβ(25-35) or HO. After confirming the neuroprotective effects of DMLS, we conducted animal studies. We administered DMLS orally at concentrations of 125, 250, and 375 mg/kg for 3 weeks. In the Y-maze test, SCO decreased spontaneous alternation, but treatment with DMLS or donepezil increased spontaneous alternation. In the Morris water-maze test, the SCO-treated group showed increased platform reach time and decreased swim time on the target platform. The passive avoidance task found that DMLS ingestion increased the recognition index in short-term memory. Furthermore, memory impairment induced by SCO reduced the ability to recognize novel objects. In the Novel Object Recognition test, recognition improved with DMLS or donepezil treatment. In the mouse brain, except for the cerebellum, acetylcholinesterase activity increased in the SCO group and decreased in the DMLS and donepezil groups. We measured catalase and malondialdehyde, which are indicators of antioxidant effectiveness, and found that oxidative stress increased with SCO but was mitigated by DMLS or donepezil treatment. Thus, our findings suggest that ingestion of DMLS restored memory impairment by protecting neuronal cells from Aβ(25-35) or HO-induced neurotoxicity, and by reducing oxidative stress.
Topics: Mice; Animals; Scopolamine; Neuroprotective Agents; Hydrogen Peroxide; Water; Acetylcholinesterase; Donepezil; Memory Disorders; Oxidative Stress; Maze Learning; Plant Extracts
PubMed: 38003650
DOI: 10.3390/ijms242216444 -
Behavioural Neurology 2023Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades....
Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades. Therefore, discovering an effective treatment with the ability to invert memory impairment and pathophysiological events of AD seems to be required. The present study performed to investigate the probable effects of Edaravone (EDV) in AD-like disorder induced by intracerebroventricular streptozotocin (ICV-STZ) administration in mice. This study also compares the two different methods of ICV-STZ in the memory impairment induction. NMRI male mice were administrated with 3 mg/kg of STZ for two times during 48 hours span, and after 24 hours, animals were treated with EDV (5 and 10 mg/kg), Donepezil, and Memantine for 14 days. After behavioral tests regarding memory and cognitive function, animals were sacrificed, and the hippocampi were utilized for further analyses. Our results demonstrated that administration of STZ induced memory impairment in the Morris water maze (MWM) test and decreased the discriminative factor in novel object recognition (NOR). The biochemical output shows a significant decrease in ferric reducing antioxidant power (FRAP) and glutathione (GSH) levels followed by increase in malondialdehyde (MDA) and protein carbonylation (PCO) levels. The output showed no difference between the patterns of AD-like disorder induction. Following our treatment groups, administration of EDV (5 and 10 mg/kg), Donepezil, and Memantine significantly improved memory performance and discriminatory behavior. Aforementioned treatments managed to improve FRAP and GSH content of hippocampus, while significantly attenuating MDA, PCO, and nitric oxide overproduction. In addition, no significant difference has been observed between the effect of 5 and 10 mg/kg EDV application. It was supposed that EDV managed to ameliorate memory dysfunction, discriminatory behavior, oxidative stress, and cellular antioxidant power in a dose-independent pattern in mice.
Topics: Rats; Male; Mice; Animals; Edaravone; Streptozocin; Antioxidants; Memantine; Rats, Wistar; Donepezil; Oxidative Stress; Memory Disorders; Alzheimer Disease; Inflammation; Maze Learning; Disease Models, Animal
PubMed: 37476485
DOI: 10.1155/2023/9652513 -
Journal of Alzheimer's Disease : JAD 2024Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD).
OBJECTIVE
We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD.
METHODS
PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence.
RESULTS
Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments- ranging from low to high certainty- showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] -0.239, 95% confidence interval [CI] -0.343 to -0.134) and lecanemab (SMD -0.194, 95% CI -0.279 to -0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo.
CONCLUSIONS
Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD.
Topics: Alzheimer Disease; Humans; Randomized Controlled Trials as Topic; Network Meta-Analysis
PubMed: 38759015
DOI: 10.3233/JAD-240161 -
Journal of Chromatography. A Sep 2023This study compares different solvent systems with the use of spontaneous fermentation on the phytochemical composition of leaf extracts from a locally grown white...
This study compares different solvent systems with the use of spontaneous fermentation on the phytochemical composition of leaf extracts from a locally grown white variety of common fig (Ficus carica Linn.). The aim was to detect and identify bioactive compounds that are responsible for acetylcholinesterase (AChE), α-amylase and cyclooxygenase-1 (COX-1) enzyme inhibition, and compounds that exhibit antimicrobial activity. Bioactive zones in chromatograms were detected by combining High-performance thin-layer chromatography (HPTLC) with enzymatic and biological assays. A new experimental protocol for measuring the relative half-maximum inhibitory concentration (IC) was designed to evaluate the potency of the extracts compared to the potency of known inhibitors. Although the IC of the fig leaf extract for α-amylase and AChE inhibition were significantly higher when compared to IC for acarbose and donepezil, the COX-1 inhibition by the extract (IC = 627 µg) was comparable to that of salicylic acid (IC = 557 µg), and antimicrobial activity of the extract (IC = 375-511 µg) was similar to ampicillin (IC = 495 µg). Four chromatographic zones exhibited bioactivity. Compounds from detected bioactive bands were provisionally identified by comparing the band positions to coeluted standards, and by Fourier transform infrared (FTIR) spectra from eluted zones. Flash chromatography was used to separate selected extract into fractions and isolate fractions that are rich in bioactive compounds for further characterisation with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) analysis. The main constituents identified were umbelliferon (zone 1), furocoumarins psoralen and bergapten (zone 2), different fatty acids (zone 3 and 4), and pentacyclic triterpenoids (calotropenyl acetate or lupeol) and stigmasterol (zone 4).
Topics: Chromatography, Thin Layer; Ficus; Plant Extracts; Acetylcholinesterase; alpha-Amylases; Pentacyclic Triterpenes; Anti-Infective Agents
PubMed: 37541060
DOI: 10.1016/j.chroma.2023.464241 -
Metabolites Sep 2023Dietary fruits and vegetables play a vital role as food and drugs and are the main sources of antioxidant defences against degenerative diseases, such as brain...
Dietary fruits and vegetables play a vital role as food and drugs and are the main sources of antioxidant defences against degenerative diseases, such as brain dysfunctions, cardiovascular diseases, immune system deteriorations, and cancers, brought on by oxidative damage. is a significant herbal remedy used in conventional medicine to recover lost strength and power. In this research, the potential value of as a food and drug is researched. The total phenolic, total flavonoid, and total tannin contents as well as the nutritional value, vitamin C, vitamin E, and mineral contents of different organs of were evaluated. The antioxidant and antimicrobial activities of extracts and fractions of different organs of were determined. A total of eleven flavonoids, simple phenolic, tannin-related phenolic, and tannin molecules were isolated from a hydroalcoholic extract of the leaves and fruits. The structures were identified by spectroscopic data and comparison with the literature values as gallic acid (), naringenin 7--(6″--galloyl)--D-glucopyranoside (), 3,3'-di--methyl ellagic acid-4'---d-glucopyranoside (), 1--galloyl glycerol (), 1,6-di--galloyl--d-glucopyranoside (), flavogallonic acid bislactone (), corilagin (), ethyl gallate (), urolithin M5 (), (E)--coumaroyl-1---d-glucopyranoside (), and 1,2,4,6-tetra--galloyl--d-glucopyranoside (). Among them, compounds and are first isolated from the plant. Molecular docking was performed to investigate the comparative interactions between positive controls (galantamine and donepezil) and selected compounds utilizing acetylcholinesterase (4EY7) as a target receptor. Results exhibited the potency of these compounds against the target receptor. In summary, has a wealth of minerals, vitamins C and E, and polyphenolic phytochemicals that may work together to treat infectious disease, prevent and/or treat oxidative-damage-related illnesses including Alzheimer's disease.
PubMed: 37755293
DOI: 10.3390/metabo13091013 -
BMC Complementary Medicine and Therapies Jul 2023This study reported the isolation and identification of bioactive compounds from Dioscorea nipponica Makino, a plant used in traditional medicine for various ailments....
This study reported the isolation and identification of bioactive compounds from Dioscorea nipponica Makino, a plant used in traditional medicine for various ailments. Nine compounds were isolated, including a new compound named as diosniposide E, which was elucidated by analyzing its H-NMR, C-NMR, DEPT, COSY, HMBC and MS data and comparing them with data available in literature. The other eight compounds were identified as known compounds. Theoretical calculations of energy and the generation of a molecular electrostatic potential surface map were employed to assess the antioxidant capacity of nine compounds, the calculation results exhibited that compounds 5 and 6 had strong antioxidant capacities. To further evaluate the antioxidant activities of the investigated compounds, the DPPH and ABTS assays were conducted. The results from the DPPH scavenging activity test revealed that compounds 4-6 exhibited enhanced scavenging activities compared to L-ascorbic acid, while displaying similar efficacy to trolox. Moreover, the ABTS scavenging activities of compounds 4-6 were found to surpass those of L-ascorbic acid and trolox. In terms of α-glucosidase inhibition, compounds 3 and 4 displayed remarkable inhibitory activities that surpassed the effects of acarbose. Additionally, compound 2 exhibited potent anticholinesterase activities, outperforming donepezil. This research provides insights into the potential bioactive compounds present in Dioscorea nipponica Makino and may contribute to its use in traditional medicine.
Topics: Dioscorea; Antioxidants; Magnetic Resonance Spectroscopy; Ascorbic Acid
PubMed: 37461036
DOI: 10.1186/s12906-023-04086-6 -
Journal of Enzyme Inhibition and... Dec 2023A library of -benzylpyridinium-based compounds, and , was designed and synthesised as potential acetylcholinesterase) AChE (inhibitors. An assay for the synthesised...
A library of -benzylpyridinium-based compounds, and , was designed and synthesised as potential acetylcholinesterase) AChE (inhibitors. An assay for the synthesised compounds showed that most compounds had significant AChE inhibitory activities at the nanomolar and submicromolar levels. The benzyl () and fluoro () derivatives were the most active, with IC values ≤56 nM. Compound which had a benzyl moiety, showed the highest potency among all the target compounds, with an IC value of 7.5 ± 0.19 nM against AChE, which was higher than that of the activities of tacrine (IC = 30 ± 0.2 nM) and donepezil (IC = 14 ± 0.12 nM). Compounds with vanillin moieties exhibited antioxidant activity. Among the tested compounds, four derivatives (, , and ) exhibited superior AChE inhibitory activity, with values of 6-16 nM, which were potent in the same range as the approved drug, donepezil. These compounds showed moderate antioxidant activities, as indicated by the results of the ABTS assay.
Topics: Humans; Donepezil; Cholinesterase Inhibitors; Antioxidants; Structure-Activity Relationship; Curcumin; Acetylcholinesterase; Pain; Alzheimer Disease; Molecular Docking Simulation
PubMed: 37985494
DOI: 10.1080/14756366.2023.2281264 -
Frontiers in Chemistry 2023A series of novel -aryl-debenzeyldonepezil derivatives () were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug...
A series of novel -aryl-debenzeyldonepezil derivatives () were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against HO-induced injury in SH-SY5Y cells. Furthermore, Compound did not show significant cytotoxicity on SH-SY5Y. These results suggest that is a potential multifunctional active molecule for treating Alzheimer's disease.
PubMed: 38144888
DOI: 10.3389/fchem.2023.1282978