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Journal of Alzheimer's Disease : JAD 2022Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance.
OBJECTIVE
We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD.
METHODS
Plasma NDEV levels of Aβ42, total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points.
RESULTS
NDEV levels of Aβ42, total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aβ42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aβ42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05).
CONCLUSION
The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.
Topics: Humans; Alzheimer Disease; Donepezil; Neurogranin; tau Proteins; Amyloid beta-Peptides; Cognitive Dysfunction; Biomarkers; Extracellular Vesicles; Peptide Fragments
PubMed: 36155516
DOI: 10.3233/JAD-220575 -
Drug Discovery Today Apr 2015For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a... (Review)
Review
For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a networks-based method to assess repeatability of outcomes across species, by intervention and mechanism. Over 75% of animal studies reported an improved outcome. Strain background was a significant potential confounder. Five percent of interventions had been tested across animals and humans, or examined across three or more animal models. Positive outcomes across species emerged for donepezil, memantine and exercise. Repeatable positive outcomes in animals were identified for the amyloid hypothesis and three additional mechanisms. This approach supports in silico reduction of positive outcomes bias in animal studies.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Data Mining; Databases, Factual; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Exercise Therapy; Humans; Indans; Memantine; Piperidines; Species Specificity; Systems Biology; Systems Integration; Translational Research, Biomedical
PubMed: 25448761
DOI: 10.1016/j.drudis.2014.10.015 -
Current Neuropharmacology 2021Crocus sativus L. (saffron) appears to own neuroprotective effects on cognitive impairment in patients with Alzheimer's disease (AD). The purpose of this work is to... (Review)
Review
Crocus sativus L. (saffron) appears to own neuroprotective effects on cognitive impairment in patients with Alzheimer's disease (AD). The purpose of this work is to review evidence and mechanisms of saffron-induced therapeutic outcomes and measureable cognitive benefits in AD. The literature was reviewed, and preclinical and clinical studies were identified. In vitro and in vivo preclinical studies were selected according to these criteria: 1) development of saffron pharmacological profile on biological or biophysical endpoints; 2) evaluation of saffron efficacy using animal screens as an AD model, and 3) duration of the studies of at least 3 months. As for the clinical studies, the selection criteria included: 1) patients aged ≥ 60, 2) AD diagnosis according to National Institute on Aging-Alzheimer's Association (NIAAA) criteria, and 3) appropriate procedures to assess cognitive, functional, and clinical status. A total of 1477 studies published until November 2020 were identified during an initial phase, of which 24 met the inclusion criteria and were selected for this review. Seventeen in vitro and in vivo preclinical studies have described the efficacy of saffron on cognitive impairment in animal models of AD, highlighting that crocin appears to be able to regulate glutamate levels, reduce oxidative stress, and modulate Aβ and tau protein aggregation. Only four clinical studies have indicated that the effects of saffron on cognitive impairment were not different from those produced by donepezil and memantine and that it had a better safety profile. Saffron and its compounds should be further investigated in order to consider them a safer alternative in AD treatment.
Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Crocus; Donepezil; Humans; Memantine
PubMed: 33441068
DOI: 10.2174/1570159X19666210113144703 -
The Journal of Neuroscience : the... Jul 2020The endogenous neurotransmitter acetylcholine (ACh) is known to affect the excitatory/inhibitory (E/I) balance of primate visual cortex, enhancing feedforward...
The endogenous neurotransmitter acetylcholine (ACh) is known to affect the excitatory/inhibitory (E/I) balance of primate visual cortex, enhancing feedforward thalamocortical gain while suppressing corticocortical synapses. Recent advances in the study of the human visual system suggest that ACh is a likely component underlying interocular interactions. However, our understanding of its precise role in binocular processes is currently lacking. Here we use binocular rivalry as a probe of interocular dynamics to determine ACh's effects, via the acetylcholinesterase inhibitor (AChEI) donepezil, on the binocular visual system. A total of 23 subjects (13 male) completed two crossover experimental sessions where binocular rivalry measurements were obtained before and after taking either donepezil (5 mg) or a placebo (lactose) pill. We report that enhanced cholinergic potentiation attenuates perceptual suppression during binocular rivalry, reducing the overall rate of interocular competition while enhancing the visibility of superimposition mixed percepts. Considering recent evidence that perceptual suppression during binocular rivalry is causally modulated by the inhibitory neurotransmitter GABA, our results suggest that cholinergic activity counteracts the effect of GABA with regards to interocular dynamics and may modulate the inhibitory drive within the visual cortex. Our research demonstrates that the cholinergic system is implicated in modulating binocular interactions in the human visual cortex. Potentiating the transmission of acetylcholine (ACh) via the cholinergic drug donepezil reduces the extent to which the eyes compete for perceptual dominance when presented two separate, incongruent images.
Topics: Acetylcholine; Adult; Cholinergic Agents; Cholinesterase Inhibitors; Cross-Over Studies; Donepezil; Female; Functional Laterality; Humans; Male; Parasympathetic Nervous System; Photic Stimulation; Psychomotor Performance; Vision Disparity; Vision, Binocular; Young Adult; gamma-Aminobutyric Acid
PubMed: 32457075
DOI: 10.1523/JNEUROSCI.2484-19.2020 -
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 -
Biomolecules May 2020Microtubule affinity-regulating kinase (MARK4) plays a key role in Alzheimer's disease (AD) development as its overexpression is directly linked to increased tau...
Microtubule affinity-regulating kinase (MARK4) plays a key role in Alzheimer's disease (AD) development as its overexpression is directly linked to increased tau phosphorylation. MARK4 is a potential drug target of AD and is thus its structural features are employed in the development of new therapeutic molecules. Donepezil (DP) and rivastigmine tartrate (RT) are acetylcholinesterase (AChE) inhibitors and are used to treat symptomatic patients of mild to moderate AD. In keeping with the therapeutic implications of DP and RT in AD, we performed binding studies of these drugs with the MARK4. Both DP and RT bound to MARK4 with a binding constant () of 10 M. The temperature dependency of binding parameters revealed MARK-DP complex to be guided by static mode while MARK-RT complex to be guided by both static and dynamic quenching. Both drugs inhibited MARK4 with IC values of 5.3 μM (DP) and 6.74 μM (RT). The evaluation of associated enthalpy change (Δ) and entropy change (Δ) implied the complex formation to be driven by hydrogen bonding making it seemingly strong and specific. Isothermal titration calorimetry further advocated a spontaneous binding. In vitro observations were further complemented by the calculation of binding free energy by molecular docking and interactions with the functionally-important residues of the active site pocket of MARK4. This study signifies the implications of AChE inhibitors, RT, and DP in Alzheimer's therapy targeting MARK4.
Topics: Binding Sites; Cholinesterase Inhibitors; Donepezil; Humans; Molecular Docking Simulation; Nootropic Agents; Protein Binding; Protein Kinase Inhibitors; RNA Helicases; Rivastigmine
PubMed: 32443670
DOI: 10.3390/biom10050789 -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2023The effects of 3,16-2-hydroxyethyl apovincaminate (HEAPO, RGH-10885) compared with those of two cholinesterase inhibitors, donepezil and galantamine, were examined in...
The effects of 3,16-2-hydroxyethyl apovincaminate (HEAPO, RGH-10885) compared with those of two cholinesterase inhibitors, donepezil and galantamine, were examined in naïve Wistar rats using standard active and passive avoidance tests. The active avoidance test (shuttle box) and two passive avoidance tests (step-through and step-down) were performed according to the experimental design. There were 10 groups of rats ( = 8) and the substances studied were applied orally before each testing session. In the active avoidance test, the number of conditioned stimuli (avoidances), unconditioned stimuli (escapes) and intertrial crossings were observed. In step-down and step-through passive avoidance tests, the latencies of reactions were observed. All the studied compounds showed positive effects in the learning and memory tests, compared to the controls. It was concluded that HEAPO, donepezil and galantamine had a memory-enhancing effect in active and passive avoidance tests.
Topics: Rats; Animals; Donepezil; Rats, Wistar; Galantamine; Avoidance Learning; Memory
PubMed: 36692469
DOI: 10.2478/acph-2023-0006 -
Current Neuropharmacology 2021The aim of this work is to review tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from...
The aim of this work is to review tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account, we summarize the efforts toward the development and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggregation, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity, cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as potential multifunctional therapeutic agents for Alzheimer's disease. Moreover, herein, we have described the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy of Alzheimer's disease based on the restoration of cholinergic function through blocking enzymes that break down acetylcholine.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Galantamine; Rivastigmine; Tacrine
PubMed: 33342413
DOI: 10.2174/1570159X19666201218103434 -
International Journal of Molecular... May 2023The extension of human life makes it more and more important to prevent and treat diseases of the elderly, including Alzheimer's disease (AD) and osteoporosis. Little is...
The extension of human life makes it more and more important to prevent and treat diseases of the elderly, including Alzheimer's disease (AD) and osteoporosis. Little is known about the effects of drugs used in the treatment of AD on the musculoskeletal system. The aim of the present study was to investigate the effects of donepezil, an acetylcholinesterase inhibitor, on the musculoskeletal system in rats with normal and reduced estrogen levels. The study was carried out on four groups of mature female rats: non-ovariectomized (NOVX) control rats, NOVX rats treated with donepezil, ovariectomized (OVX) control rats and OVX rats treated with donepezil. Donepezil (1 mg/kg p.o.) was administered for four weeks, starting one week after the ovariectomy. The serum concentrations of CTX-I, osteocalcin and other biochemical parameters, bone mass, density, mineralization, histomorphometric parameters and mechanical properties, and skeletal muscle mass and strength were examined. Estrogen deficiency increased bone resorption and formation and worsened cancellous bone mechanical properties and histomorphometric parameters. In NOVX rats, donepezil decreased bone volume to tissue volume ratio in the distal femoral metaphysis, increased the serum phosphorus concentration and tended to decrease skeletal muscle strength. No significant bone effects of donepezil were observed in OVX rats. The results of the present study indicate slightly unfavorable effects of donepezil on the musculoskeletal system in rats with normal estrogen levels.
Topics: Humans; Rats; Female; Animals; Aged; Donepezil; Rats, Sprague-Dawley; Acetylcholinesterase; Bone and Bones; Bone Density; Estrogens; Ovariectomy
PubMed: 37240337
DOI: 10.3390/ijms24108991 -
Journal of the Royal Society of Medicine Oct 1997
Review
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cost-Benefit Analysis; Donepezil; Drug Monitoring; Humans; Indans; Informed Consent; Piperidines
PubMed: 9488008
DOI: 10.1177/014107689709001002