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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 -
Molecular Pharmaceutics Sep 2023This work focuses on developing nanoemulsions using a low-energy emulsification method for the codelivery of donepezil and memantine in one dosage form intended to be...
This work focuses on developing nanoemulsions using a low-energy emulsification method for the codelivery of donepezil and memantine in one dosage form intended to be administered via the intranasal route for enhanced brain delivery. The nanoemulsion formulation was prepared using a low emulsification technique and characterized using various microscopy and nasal ciliotoxicity studies. The safe nanoemulsion was intended for preclinical pharmacokinetics with brain distribution and pharmacodynamics in a scopolamine-induced murine model. The formulated nanoemulsion was 16 nm in size, with a zeta potential of -7.22 mV, and exhibited a spherical shape. The brain concentration of IN-administered NE for DPZ and MEM was ∼678 and 249 ng/mL after 15 min. This concentration is more than 2 times higher in amount when compared with NE administered via PO, free drug solution administered via IN and PO route both. However, the plasma concentration of IN-administered NE for DPZ and MEM was ∼3 and 28 ng/mL after 15 min. In pharmacodynamic studies, the efficacy of NE administered via the IN route was higher when compared with other groups in neurobehavioral, biochemical estimation, and gene expression studies. The results suggest that the IN route can be explored in the future for the delivery of actives via nanocolloidal carriers in the brain for neurological disorders and can serve as promising alternatives for conventional dosage forms and routes.
Topics: Mice; Animals; Donepezil; Memantine; Administration, Intranasal; Brain; Scopolamine; Emulsions; Nanoparticles; Particle Size
PubMed: 37523676
DOI: 10.1021/acs.molpharmaceut.3c00454 -
Journal of Chemical Information and... Jul 2020Donepezil is a second generation acetylcholinesterase (AChE) inhibitor for treatment of Alzheimer's disease (AD). AChE is important for neurotransmission at...
Donepezil is a second generation acetylcholinesterase (AChE) inhibitor for treatment of Alzheimer's disease (AD). AChE is important for neurotransmission at neuromuscular junctions and cholinergic brain synapses by hydrolyzing acetylcholine into acetate and choline. data support that donepezil is a reversible, mixed competitive and noncompetitive inhibitor of AChE. The experimental fact then suggests a more complex binding mechanism beyond the molecular view in X-ray models resolved at cryogenic temperatures that show a unique binding mode of donepezil in the active site of the enzyme. Aiming at clarifying the mechanism behind that mixed competitive and noncompetitive nature of the inhibitor, we have applied molecular dynamics (MD) simulations and docking and free-energy calculations to investigate microscopic details and energetics of donepezil association for conditions of substrate-free and -bound states of the enzyme. Liquid-phase MD simulation at room temperature shows AChE transits between "open" and "closed" conformations to control accessibility to the active site and ligand binding. As shown by docking and free-energy calculations, association of donepezil involves its reversible axial displacement and reorientation in the active site of the enzyme, assisted by water molecules. Donepezil binds equally well the main-door anionic binding site PAS, the acyl pocket, and the catalytic site CAS by respectively adopting -- orientations regardless of substrate occupancy-the overall stability of that reaction process depends however on co-occupancy of the enzyme being preferential for its substrate-free state. All together, our findings support a physiologically relevant mechanism of AChE inhibition by donepezil involving multistable interactions modes at the molecular origin of the inhibitor's activity.
Topics: Acetylcholinesterase; Alzheimer Disease; Binding Sites; Cholinesterase Inhibitors; Donepezil; Humans; Temperature
PubMed: 32096991
DOI: 10.1021/acs.jcim.9b01073 -
Naunyn-Schmiedeberg's Archives of... Mar 2021Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer's dementia by increasing acetylcholine concentrations in the central nervous system....
Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer's dementia by increasing acetylcholine concentrations in the central nervous system. However, it is becoming apparent that cholinesterase inhibition by donepezil is not confined to the brain. This is supported by previous case reports of peripheral cholinergic side effects and adverse cardiac arrhythmias such as Torsades de Pointes which are reversible upon cessation of donepezil. The augmented acetylcholine concentrations and I inhibition in cardiomyocytes caused by donepezil are believed to mediate this effect.
Topics: Alzheimer Disease; Animals; Arrhythmias, Cardiac; Atrioventricular Block; Cholinesterase Inhibitors; Dogs; Donepezil; Halothane; Indans; Piperidines
PubMed: 33230575
DOI: 10.1007/s00210-020-02028-4 -
Biomaterials Advances Nov 2023The current work is focused on developing mannose-coated PLGA nanoparticles for delivering Donepezil and Memantine in one dosage form. The formulated nanoparticles were...
The current work is focused on developing mannose-coated PLGA nanoparticles for delivering Donepezil and Memantine in one dosage form. The formulated nanoparticles were prepared using a simple emulsification technique. The final coated NPs exhibited 179.4 nm size and - 33.1 mV zeta potential and spherical shape. The concentration of IN-administrated MEM and DPZ mannose coated NPs in brain was ~573 and 207 ng/mL respectively. This amount accounts for 3 times more in comparison to uncoated NPs administered via intranasal and peroral routes. The plasma concentration of coated NPs administered via the intranasal route was various times less in comparison to other groups. In the field of pharmacodynamics, the administration of coated NPs via the IN route has shown superior efficacy in comparison to other groups in various investigations involving neurobehavioral assessments, gene expression analyses and biochemical estimations. The findings indicate that the IN route may be a potential avenue for delivering therapeutic agents using nanoparticles to treat neurological illnesses. This approach shows promise as a viable alternative to traditional dose forms and administration methods.
Topics: Donepezil; Memantine; Polylactic Acid-Polyglycolic Acid Copolymer; Polyglycolic Acid; Lactic Acid; Mannose; Nanoparticles
PubMed: 37865027
DOI: 10.1016/j.bioadv.2023.213663 -
Neurotoxicity Research Dec 2022Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment....
Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.
Topics: Humans; Donepezil; Memantine; Alzheimer Disease; Piperidines; Indans; Cognitive Dysfunction; MicroRNAs; Cholinesterase Inhibitors
PubMed: 36367679
DOI: 10.1007/s12640-022-00591-7 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2022Alzheimer's disease is one of the most common neurodegenerative diseases worldwide and carries a huge social burden. Unfortunately, no disease-modifying drug has been...
Alzheimer's disease is one of the most common neurodegenerative diseases worldwide and carries a huge social burden. Unfortunately, no disease-modifying drug has been approved so far. Currently approved medications are symptomatic and include two classes: cholinesterase inhibitors, such as donepezil, and NMDA receptor antagonist memantine. Most studies have shown that a combination of both classes is better than monotherapy. The review discusses the pharmacological properties, efficacy and safety data of memantine and donepezil.
Topics: Humans; Alzheimer Disease; Memantine; Donepezil; Cholinesterase Inhibitors; Drug Therapy, Combination
PubMed: 36412156
DOI: 10.17116/jnevro202212211245 -
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 -
CNS & Neurological Disorders Drug... 2020Alzheimer's disease is a neuropathological disease with symptoms such as language problems, confusion as to place or time, loss of interest in activities, which were... (Review)
Review
Alzheimer's disease is a neuropathological disease with symptoms such as language problems, confusion as to place or time, loss of interest in activities, which were previously enjoyed, behavioral changes, and memory loss. Alzheimer's disease and other types of dementia affect almost 46.8 million people globally and are estimated to strike about 131.5 million people in 2050. It has been reported that Alzheimer's is the sixth main cause of mortality. The most used drugs, which are currently approved by the Food, and Drug Administration for Alzheimer's disease are donepezil, rivastigmine, galantamine, memantine, and the combination of donepezil and memantine. However, most of the drugs present various adverse effects. Recently, the transdermal drug delivery route has gained increasing attention as an emerging tool for Alzheimer's disease management. Besides, transdermal drug delivery systems seem to provide hope for the management of various diseases, due to the advantages that they offer in comparison with oral dosage forms. Herein, the current advancements in transdermal studies with potent features to achieve better Alzheimer's disease management are presented. Many researchers have shown that the transdermal systems provide higher efficiency since the first-pass hepatic metabolism effect can be avoided and a prolonged drug release rate can be achieved. In summary, the transdermal administration of Alzheimer's drugs is an interesting and promising topic, which should be further elaborated and studied.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Delivery Systems; Humans; Memantine; Rivastigmine
PubMed: 32552655
DOI: 10.2174/1871527319666200618150046