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ELife Dec 2023Perceptual decisions about sensory input are influenced by fluctuations in ongoing neural activity, most prominently driven by attention and neuromodulator systems. It...
Perceptual decisions about sensory input are influenced by fluctuations in ongoing neural activity, most prominently driven by attention and neuromodulator systems. It is currently unknown if neuromodulator activity and attention differentially modulate perceptual decision-making and/or whether neuromodulatory systems in fact control attentional processes. To investigate the effects of two distinct neuromodulatory systems and spatial attention on perceptual decisions, we pharmacologically elevated cholinergic (through donepezil) and catecholaminergic (through atomoxetine) levels in humans performing a visuo-spatial attention task, while we measured electroencephalography (EEG). Both attention and catecholaminergic enhancement improved decision-making at the behavioral and algorithmic level, as reflected in increased perceptual sensitivity and the modulation of the drift rate parameter derived from drift diffusion modeling. Univariate analyses of EEG data time-locked to the attentional cue, the target stimulus, and the motor response further revealed that attention and catecholaminergic enhancement both modulated pre-stimulus cortical excitability, cue- and stimulus-evoked sensory activity, as well as parietal evidence accumulation signals. Interestingly, we observed both similar, unique, and interactive effects of attention and catecholaminergic neuromodulation on these behavioral, algorithmic, and neural markers of the decision-making process. Thereby, this study reveals an intricate relationship between attentional and catecholaminergic systems and advances our understanding about how these systems jointly shape various stages of perceptual decision-making.
Topics: Humans; Attention; Electroencephalography; Donepezil; Atomoxetine Hydrochloride; Neurotransmitter Agents; Decision Making
PubMed: 38038722
DOI: 10.7554/eLife.87022 -
Healthcare (Basel, Switzerland) Jul 2023Behavioral and psychological symptoms of dementia are a major factor in the burden of care and medical expenses. Conventional pharmacological treatments do not exert a...
Efficacy and Safety of Woohwangchungsimwon Combined with Donepezil in Behavioral and Psychological Symptoms of Dementia in Patients with Probable Alzheimer's Disease: Study Protocol for a Randomized Controlled Trial.
Behavioral and psychological symptoms of dementia are a major factor in the burden of care and medical expenses. Conventional pharmacological treatments do not exert a distinct effect on the benefits versus the risks. The herbal medicine woohwangchungsimwon is frequently prescribed for neuropsychiatric disorders. An effect of woohwangchungsimwon on behavioral and psychological symptoms of dementia has been previously reported; however, no clinical studies have been conducted. We aim to evaluate the efficacy and safety of woohwangchungsimwon combined with donepezil for alleviating these symptoms in probable Alzheimer's disease. In this randomized, assessor-blinded, parallel-group clinical trial, 74 participants with probable Alzheimer's disease will be divided via block randomization into a woohwangchungsimwon + donepezil combination group (n = 37) or a donepezil single group (n = 37). Participants will include patients under donepezil treatment for at least a month. We will perform the study for 24 weeks. The Neuro-Psychiatric Inventory subscale scores will be the primary outcome. Secondary outcomes will include cognitive function, dementia severity, physical function, quality of life, depression, anxiety, and insomnia. For safety evaluation, we will assess adverse reactions, measure vital signs, and conduct laboratory tests. This is the first trial aiming to confirm the efficacy and safety of woohwangchungsimwon combined with donepezil for alleviating behavioral and psychological symptoms of dementia. Its findings could provide a basis for their co-administration to control these symptoms in probable Alzheimer's disease.
PubMed: 37510478
DOI: 10.3390/healthcare11142036 -
Molecular Biology Reports Jan 2024Alzheimer's disease's pathophysiology is still a conundrum. Growing number of evidences have elucidated the involvement of oxidative stress in the pathology of AD... (Review)
Review
Alzheimer's disease's pathophysiology is still a conundrum. Growing number of evidences have elucidated the involvement of oxidative stress in the pathology of AD rendering it a major target for therapeutic development. Reactive oxygen species (ROS) generated by altered mitochondrial function, dysregulated electron transport chain and other sources elevate aggregated Aβ and neurofibrillary tangles which further stimulating the production of ROS. Oxidative stress induced damage to lipids, proteins and DNA result in neuronal death which leads to AD. In addition, oxidative stress induces apoptosis that is triggered by the modulation of ERK1/2 and Nrf2 pathway followed by increased GSK-3β expression and decreased PP2A activity. Oxidative stress exaggerates disease condition by interfering with various signaling pathways like RCAN1, CREB/ERK, Nrf2, PP2A, NFκB and PI3K/Akt. Studies have reported the role of TNF-α in oxidative stress stimulation that has been regulated by drugs like etanercept increasing the level of anti-oxidants. Other drugs like pramipexole, memantine, carvedilol, and melatonin have been reported to activate CREB/RCAN1 and Nrf2 pathways. In line with this, epigallocatechin gallate and genistein also target Nrf2 and CREB pathway leading to activation of downstream pathways like ARE and Keap1 which ameliorate oxidative stress condition. Donepezil and resveratrol reduce oxidative stress and activate AMPK pathway along with PP2A activation thus promoting tau dephosphorylation and neuronal survival. This study describes in detail the role of oxidative stress in AD, major signaling pathways involving oxidative stress induced AD and drugs under development targeting these pathways which may aid in therapeutic advances for AD.
Topics: Humans; Alzheimer Disease; Kelch-Like ECH-Associated Protein 1; Reactive Oxygen Species; Glycogen Synthase Kinase 3 beta; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Oxidative Stress; Signal Transduction
PubMed: 38165499
DOI: 10.1007/s11033-023-09021-z -
Cureus Jul 2023Background Dementia is an age-related gradual loss of memory that is progressive in nature. Presently, the most common cause of dementia is Alzheimer's disease (AD),...
Background Dementia is an age-related gradual loss of memory that is progressive in nature. Presently, the most common cause of dementia is Alzheimer's disease (AD), which is treated with donepezil, an anticholinesterase. But it only provides short-term symptomatic improvement. Liraglutide, which is an anti-diabetic drug, stimulates the anti-apoptotic pathway of nerve damage, which helps in regenerating nerve cells; so, it may help in dementia cases. Therefore, this study aimed to explore the effect of liraglutide on learning and memory and to compare its effect with donepezil in diazepam-induced amnesic albino rats. Methodology Twenty healthy male Albino rats weighing 150-200 grams were taken and divided into four groups: A, B, C, and D. Group A rats were normal rats, whereas the rats in groups B, C, and D were made amnesic by the intraperitoneal (i.p.) administration of 0.1 mg per kg of diazepam. Immediately after producing amnesia, group B rats received normal saline, group C received liraglutide, and group D received donepezil through the intraperitoneal route as test drugs. Group A rats received only normal saline. The amnesic effect was measured by the escape latency period, which was measured by using a Morris Water Maize (MWM) instrument. Escape latency is the time (in seconds) to locate the platform from the starting point. The amnesic effect is shown by an increase in escape latency and the anti-amnesic effect by a decrease in escape latency. Escape latency was recorded at 0 hr, 1 hr, 2 hr, 3 hr, and 4 hr after test drug administration. Results Group B rats showed an increase in escape latency, which shows the amnesic effect of diazepam. When group C and group D amnesic rats were treated with liraglutide and donepezil, respectively, a one-hour after-treatment increase in escape latency was seen but after two hours, both groups showed a decrease in escape latency, which indicates the anti-amnesic effect of both drugs. When groups C and D were compared, and the post-hoc highly significant difference (HSD) test was used, there was no significant difference between the two drugs, although the liraglutide-treated group (C) showed a lower anti-amnesic effect. However, group C showed a significant effect as compared to group B rats (p-value <0.05), which indicates the anti-amnesic property of liraglutide as compared to normal saline. Conclusion Liraglutide shows an anti-amnesic property. Since it works by a mechanism different from donepezil, it can be used as add-on therapy with donepezil in dementia patients.
PubMed: 37551235
DOI: 10.7759/cureus.41495 -
Journal of Pharmaceutical and... Oct 2023Alzheimer's disease (AD) is a progressive disease with continuous brain changes and has caused a severe burden on families and society. Huanglian Jiedu Decoction (HLJD)...
Alzheimer's disease (AD) is a progressive disease with continuous brain changes and has caused a severe burden on families and society. Huanglian Jiedu Decoction (HLJD) is a classic traditional Chinese medicine formula that can improve AD animals' cognitive impairment. This study recruited 50 AD patients who were divided into two groups, one receiving donepezil (DON) treatment and the other receiving DON + HLJD treatment for 3 months. The curative effect, inflammatory and oxidative stress levels were analyzed. The PES-D/11, MMSE, and ADL scales were used to evaluate traditional Chinese medicine syndrome elements, cognitive function, mental state, and life ability. There were no significant differences between the two groups in baseline characteristics and vital sign indicators. After drug treatment, the results showed that AD patients with HLJD combined with DON treatment didn't increase the adverse effects and had good compliance. HLJD combined with DON could improve the disease syndrome, making the differences in PES-D/11, MMSE, and ADL scores before and after the intervention larger. Furthermore, both DON and DON+HLJD treatment inhibited the levels of IL-6, IL-1β, TNF-α, and MDA, raised SOD level, and HLJD enhances the inhibitory effect of DON on inflammation and oxidative stress. IL-6, IL-1β, TNF-α, and MDA levels were significantly correlated with curative effect. Moreover, this study found 107 (206) up-regulated metabolites and 1430 (145) down-regulated metabolites in urine (serum) and conducted differential metabolite screening and correlation analysis suggesting that HLJD may interfere with oxidative stress and inflammation in AD by regulating lipid metabolism and glutamic acid metabolism. Arachidonic acid, diaminopimelic acid, and 1-Aminocyclopropanecarboxylic acid may play an important role in HLJD to improve AD.
Topics: Animals; Alzheimer Disease; Donepezil; Tumor Necrosis Factor-alpha; Interleukin-6; Drugs, Chinese Herbal; Metabolomics; Inflammation
PubMed: 37542831
DOI: 10.1016/j.jpba.2023.115610 -
Pathology International Nov 2023This article focuses on the specific effects and mechanisms of donepezil (DNPZ) hydrochloride on inflammation and apoptosis in ulcerative colitis (UC). In vivo and in...
This article focuses on the specific effects and mechanisms of donepezil (DNPZ) hydrochloride on inflammation and apoptosis in ulcerative colitis (UC). In vivo and in vitro models of UC were established using dextran sodium sulfate (DSS)-induced mice and NCM460 cells, respectively. Following oral administration of DNPZ, body weight, disease activity index (DAI) scores and colon lengths of mice were recorded. Histopathological damage was detected employing hematoxylin and eosin (H&E) staining. Inflammatory factors were tested using enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction, respectively. Apoptosis was estimated utilizing terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot. Low-density lipoprotein receptor-related protein 1 (LRP1)/AMP activated protein kinase (AMPK)/nuclear factor-κB (NF- κB) signaling proteins were detected utilizing western blot. NCM460 cell viability was assessed by cell counting kit (CCK)-8. We found that DNPZ partially restored body weight, reduced DAI scores and attenuated intestinal pathological damage in DSS-induced mice. Additionally, inflammatory factors decreased significantly after DNPZ treatment, accompanied by reduced apoptosis level. Phosphorylation (p)-AMPK increased and p-p65 decreased after DNPZ treatment, whereas LRP1 knockdown showed the opposite effect. Moreover, DNPZ treatment greatly restored NCM460 cell viability after DSS stimulation. DNPZ attenuated DSS-induced inflammation and apoptosis in NCM460 cells, which was reversed by LRP1 knockdown. In summary, DNPZ hydrochloride attenuates inflammation and apoptosis in UC via LRP1/AMPK/NF-κB signaling.
Topics: Mice; Animals; Colitis, Ulcerative; NF-kappa B; AMP-Activated Protein Kinases; Donepezil; Colon; Inflammation; Apoptosis; Body Weight; Disease Models, Animal; Colitis; Mice, Inbred C57BL
PubMed: 37830504
DOI: 10.1111/pin.13380 -
European Review For Medical and... Mar 2024Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter...
OBJECTIVE
Alzheimer's disease (AD) is identified by neuropathological symptoms, and there is now no effective treatment for the condition. A lack of the brain neurotransmitter acetylcholine has been related to the etiology of Alzheimer's disease. Acetylcholinesterase is an enzyme that breaks down acetylcholine to an inactive form and causes the death of cholinergic neurons. Conventional treatments were used but had less effectiveness. Therefore, there is a crucial need to identify alternative compounds with potential anti-cholinesterase agents and minimal undesirable effects.
MATERIALS AND METHODS
Fluoroquinolones and benzimidazole-benzothiazole derivatives offer antimicrobial, anti-inflammatory, anti-oxidant, anti-diabetic, and anti-Alzheimer activities. To enhance the chemical portfolio of cholinesterase inhibitors, a variety of fluoroquinolones and benzimidazole-benzothiazole compounds were evaluated against acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzymes. For this purpose, molecular docking and adsorption, distribution, metabolism, excretion, and toxicology ADMET models were used for in-silico studies for both AChE and BChE enzymes to investigate possible binding mechanisms and drug-likeness of the compounds. The inhibitory effect of docked heterocyclic compounds was also verified in vitro against AChE and BChE enzymes. Fluoroquinolones (Z, Z3, Z4, Z6, Z8, Z12, Z15, and Z9) and benzimidazole-benzothiazole compounds (TBIS-16, TBAF-1 to 9) passed through the AChE inhibition assay and their IC50 values were calculated.
RESULTS
The compound 1-ethyl-6-fluoro-7-(4-(2-(4-nitrophenylamino)-2-oxoethyl)piperazin-1-yl) -4-oxo-1,4 di-hydroquinoline-3-carboxylic acid and 2-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(3-bromobenzyl)-4-hydroxy-2H-thiochromene-3-carbohydrazide 1,1-dioxide (Z-9 and TBAF-6) showed the lowest IC50 values against AChE/BChE (0.37±0.02/2.93±0.03 µM and 0.638±0.001/1.31±0.01 µM, respectively) than the standard drug, donepezil (3.9±0.01/4.9±0.05 µM). During the in-vivo investigation, behavioral trials were performed to analyze the neuroprotective impact of Z-9 and TBAF-6 compounds on AD mouse models. The groups treated with Z-9 and TBAF-6 compounds had better cognitive behavior than the standard drug.
CONCLUSIONS
This study found that Z-9 (Fluoroquinolones) and TBAF-6 (benzimidazole-benzothiazole) compounds improve behavioral and biochemical parameters, thus treating neurodegenerative disorders effectively.
Topics: Mice; Animals; Cholinesterase Inhibitors; Acetylcholinesterase; Butyrylcholinesterase; Alzheimer Disease; Acetylcholine; Molecular Docking Simulation; Benzothiazoles; Benzimidazoles; Fluoroquinolones; Structure-Activity Relationship
PubMed: 38567612
DOI: 10.26355/eurrev_202403_35759 -
Frontiers in Neuroscience 2023Prior research has shown mixed results regarding the effectiveness of combining donepezil and traditional Chinese medicine (TCM) to treat mild cognitive impairment... (Review)
Review
OBJECTIVE
Prior research has shown mixed results regarding the effectiveness of combining donepezil and traditional Chinese medicine (TCM) to treat mild cognitive impairment (MCI). In light of this, our study aims to examine the efficacy and safety of this treatment approach for patients with MCI.
METHODS
We conducted a comprehensive search of various databases, including Medline ( PubMed), Cochrane, Embase, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and Wanfang Database from their inception to November 16, 2022. The selection of studies, risk of bias assessment, and data extraction were carried out independently by two authors. The statistical analysis was performed using STATA.
RESULTS
Our meta-analysis included a total of 35 studies with 2,833 patients, published between 2008 and 2022, with intervention durations ranging from 4 weeks to 12 months. However, most of the studies had a high risk of detection bias. Our findings indicated that the combination of donepezil and TCM significantly improved the Montreal Cognitive Assessment (MoCA) score (weighted mean difference [WMD] = 2.79, 95% confidence interval [CI]: 1.82 to 3.75) and the Barthel Index score (WMD = 9.20, 95% CI: 5.39 to 13.00) compared to donepezil alone. However, subgroup analyses showed that the MoCA score did not increase significantly in patients with MCI resulting from cerebrovascular disease (WMD = 1.47, 95% CI: -0.02 to 2.96).
CONCLUSION
The combination of donepezil and TCM may have a more positive effect on cognitive function and activities of daily living in patients with MCI compared to the use of donepezil alone. However, due to the limited quality of the studies included in our analysis, these findings should be interpreted with caution.
PubMed: 37476835
DOI: 10.3389/fnins.2023.1206491 -
Food and Chemical Toxicology : An... Jul 2024An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into...
An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.
Topics: Animals; Donepezil; Doxorubicin; Male; Rats, Wistar; Gastrointestinal Microbiome; Rats; Fatty Acids, Volatile; Dysbiosis; Methylamines; Endotoxins
PubMed: 38759714
DOI: 10.1016/j.fct.2024.114741 -
ACS Biomaterials Science & Engineering Jul 2023Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug...
Liver-related drug metabolism is a key aspect of pharmacokinetics and possible toxicity. From this perspective, the availability of advanced in vitro models for drug testing is still an open need, also to the end of reducing the burden of in vivo experiments. In this scenario, organ-on-a-chip is gaining attention as it couples a state-of-the art in vitro approach to the recapitulation of key in vivo physiological features such as fluidodynamics and a tri-dimensional cytoarchitecture. We implemented a novel liver-on-a-chip (LoC) device based on an innovative dynamic device (MINERVA 2.0) where functional hepatocytes (iHep) have been encapsulated into a 3D hydrogel matrix interfaced through a porous membrane with endothelial cells (iEndo)]. Both lines were derived from human-induced pluripotent stem cells (iPSCs), and the LoC was functionally assessed with donepezil, a drug approved for Alzheimer's disease therapy. The presence of iEndo and a 3D microenvironment enhanced the expression of liver-specific physiologic functions as in iHep, after 7 day perfusion, we noticed an increase of albumin, urea production, and cytochrome CYP3A4 expression compared to the iHep static culture. In particular, for donepezil kinetics, a computational fluid dynamic study conducted to assess the amount of donepezil diffused into the LoC indicated that the molecule should be able to pass through the iEndo and reach the target iHep construct. Then, we performed experiments of donepezil kinetics that confirmed the numerical simulations. Overall, our iPSC-based LoC reproduced the in vivo physiological microenvironment of the liver and was suitable for potential hepatotoxic screening studies.
Topics: Humans; Induced Pluripotent Stem Cells; Alzheimer Disease; Donepezil; Endothelial Cells; Liver; Lab-On-A-Chip Devices
PubMed: 37318190
DOI: 10.1021/acsbiomaterials.3c00346