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Frontiers in Behavioral Neuroscience 2020When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding... (Review)
Review
When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment. Our data therefore suggest a Janus-faced dose-response curve for donepezil in depression-related behavior. In this review, we investigate the mood-related properties of AChEIs in greater detail, focusing on both human and rodent studies. In fact, while there have been many studies showing pro-depressant activity by AChEIs and this is a major concept in the field, a variety of other studies in both humans and rodents show antidepressant effects. Our study was one of the first to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant roles for AChEIs in rodents may provide hope for new depression treatments. Importantly, MDD is a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying depression mechanisms, so an important future direction will be to determine the extent to which these depression-related effects are stress-sensitive. In sum, gaining a greater understanding of the potentially therapeutic mood-related effects of low dose AChEIs, both in rodent models and in human subjects, should be a prioritized topic in ongoing translational research.
PubMed: 33519395
DOI: 10.3389/fnbeh.2020.620119 -
Oxford Medical Case Reports Sep 2023Antimuscarinic drug toxicity is a common pediatric emergency, which produces central and peripheral symptoms. Treatment of agitation and hyperactive antimuscarinic...
Antimuscarinic drug toxicity is a common pediatric emergency, which produces central and peripheral symptoms. Treatment of agitation and hyperactive antimuscarinic delirium, with first-line agents like cholinesterase inhibitors or benzodiazepines, is imperative to prevent severe toxicity. Intravenous physostigmine salicylate is a cholinesterase inhibitor that is commonly used to treat central antimuscarinic delirium. Its chemical structure facilitates crossing of the blood-brain barrier. Overlapping nationwide physostigmine and benzodiazepine shortages have prompted consideration of therapeutic alternatives. Rivastigmine is a long-acting cholinesterase inhibitor with a similar chemical structure to physostigmine. It represents a potential therapeutic option for antimuscarinic delirium. Rivastigmine offers potential benefits over physostigmine including a longer duration of action, slower rate of central nervous system penetration, more favorable side effect profile, and availability in multiple formulations. A paucity of literature exists describing the use of rivastigmine for central antimuscarinic delirium. We describe the effective use of oral rivastigmine in a child with central antimuscarinic delirium.
PubMed: 37771682
DOI: 10.1093/omcr/omad096 -
Journal of the Academy of... 2021Second-generation antipsychotic agents are commonly used by clinicians for the treatment of various psychiatric and medical conditions. Despite their presumed safety, an... (Review)
Review
BACKGROUND
Second-generation antipsychotic agents are commonly used by clinicians for the treatment of various psychiatric and medical conditions. Despite their presumed safety, an overdose with olanzapine may lead to the development of anticholinergic toxicity. The anticholinergic toxidrome is characterized by both central and peripheral physical findings. Central anticholinergic syndrome, a term used to describe the symptoms that arise from reduced cholinergic activity in the central nervous system, is characterized primarily by signs and symptoms consistent with hyperactive delirium. Signs of peripheral anticholinergia include mydriasis and blurred vision, tremors, ataxia, fever/hyperthermia, flushed and dry skin, dry oral mucosa, decreased bowel sounds, constipation, and urinary retention, among other symptoms. In extreme cases, central anticholinergic syndrome can be associated with seizures, coma, respiratory failure, and cardiovascular collapse.
OBJECTIVE
To provide scientific evidence regarding the efficacy and safety of physostigmine use in cases of anticholinergic toxicity.
METHODS
We conducted a comprehensive review of the published literature on the symptoms, diagnosis, and treatment of anticholinergic toxicity.
RESULTS
Currently the recommended treatment for olanzapine overdose, as is the case of most severe anticholinergic toxicity cases, involves supportive care, along with cardiac, neurological, and respiratory status monitoring. In addition, we detail the symptoms characteristic of anticholinergic toxicity, using the case of a patient experiencing central anticholinergic syndrome after an overdose with olanzapine.
CONCLUSION
Physostigmine, a tertiary acetylcholinesterase inhibitor, can be used to assist in the both the diagnosis and management of severe anticholinergic toxicity associated with an olanzapine overdose, which might be applicable to the antimuscarinic toxidrome associated with the ingestion of agents with significant anticholinergic activity.
Topics: Acetylcholinesterase; Anticholinergic Syndrome; Cholinergic Antagonists; Humans; Olanzapine; Physostigmine
PubMed: 34102130
DOI: 10.1016/j.jaclp.2020.12.013 -
British Journal of Clinical Pharmacology Jan 2022Physostigmine is the preferred treatment for antimuscarinic toxicity. Its use has a clear biological rationale and is supported by extensive clinical use which...
Physostigmine is the preferred treatment for antimuscarinic toxicity. Its use has a clear biological rationale and is supported by extensive clinical use which demonstrated effectiveness and safety.
Topics: Cholinesterase Inhibitors; Humans; Muscarinic Antagonists; Physostigmine
PubMed: 34705298
DOI: 10.1111/bcp.15120 -
RSC Advances May 2020Synthesis of a compound with balanced bioactivities against a specific target is always a challenging task. In this study, a novel compound (1) has been synthesized by...
Synthesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities, and molecular docking studies of a novel compound based on combination of flurbiprofen and isoniazide.
Synthesis of a compound with balanced bioactivities against a specific target is always a challenging task. In this study, a novel compound (1) has been synthesized by combination of flurbiprofen and isoniazide and shows ∼2.5 times enhanced acetylcholinesterase (AChE) inhibition activity and ∼1.7 times improved butyrylcholinesterase (BuChE) inhibition activity compared to flurbiprofen and a standard drug ( physostigmine). A comparative AutoDock study has been performed, based on the optimized structure, by the DFT/B3LYP method, which confirmed that compound (1) is more active against AChE and BuChE, with calculated binding energies of -12.9 kcal mol and -9.8 kcal mol respectively as compared to flurbiprofen and an eserine (physostigmine) standard for which the binding energy was calculated to be -10.1 kcal mol and -8.9 kcal mol, respectively. A mixed mode of inhibition of AChE and BuChE with compound 1 was confirmed by Lineweaver-Burk plots. AChE and BuChE inhibition activity alongside docking results suggests that compound (1) could be used for treatment of Alzheimer's disease. Moreover, compound (1) also exhibit better α-chymotrypsin activity compared to flurbiprofen. Furthermore, and analysis confirmed that compound (1) exhibit more activity and less toxicity than the parent compounds.
PubMed: 35515452
DOI: 10.1039/d0ra02339f -
Future Medicinal Chemistry Aug 2019Alzheimer's disease (AD) is known to be themajor cause of dementia among the elderly. The structural properties and binding interactions of the AD drug physostigmine...
Alzheimer's disease (AD) is known to be themajor cause of dementia among the elderly. The structural properties and binding interactions of the AD drug physostigmine (-)-phy, and its analogues (-)-hex and (-)-phe and (+)-phe, were examined, as well as their impact on the conformational changes of two different AD target enzymes AChE and BChE. The conformational changes were studied using molecular dynamics and structural properties using Quantum mechanics. The binding free energy (ΔGbind) and the change in the free energy surface (FES) computed from the funnel metadynamics (FMD) simulation, both support the idea that inhibitors (-)-phe and (-)-hex have better binding activities toward enzyme AChE, and that (-)-phe is stronger in binding than the present AD drug (-)-phy.
Topics: Acetylcholinesterase; Alzheimer Disease; Binding Sites; Butyrylcholinesterase; Cholinesterase Inhibitors; Cluster Analysis; Humans; Ligands; Molecular Dynamics Simulation; Physostigmine; Principal Component Analysis; Protein Binding; Quantum Theory; Thermodynamics
PubMed: 31517530
DOI: 10.4155/fmc-2018-0421 -
Chemical Communications (Cambridge,... Aug 2022Utilization of Freon-type methanes as functional one-carbon synthons in the synthesis of various deuterated indoline alkaloids was demonstrated here. A series of...
Utilization of Freon-type methanes as functional one-carbon synthons in the synthesis of various deuterated indoline alkaloids was demonstrated here. A series of halomethyl radicals were generated from electro-reductive C-X cleavage of Freon-type methanes and captured efficiently by acrylamides to provide various halogenated oxindoles radical cyclization. This reaction features good functional group tolerance, and deuterium and fluorine atoms could be introduced facilely from Freon-type methanes. Further transformation of halogenated oxindoles enabled the synthesis of many (labeled) bioactive drug molecules and skeletons, such as deuterated (±)-physostigmine, deuterated (±)-esermethole and deuterated (±)-lansai B.
Topics: Alkaloids; Chlorofluorocarbons; Methane; Oxindoles; Stereoisomerism
PubMed: 35899819
DOI: 10.1039/d2cc03301a -
The Journal of Pharmacology and... May 2023Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of...
Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 μg and 2 μg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 μM, 10 μM, 30 μM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 μM/side) coadministration with physostigmine (2 μg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.
Topics: Female; Rats; Male; Animals; Ventral Tegmental Area; Nucleus Accumbens; Dopamine; Receptor, Muscarinic M5; Acetylcholine; Physostigmine; Rats, Sprague-Dawley
PubMed: 36828630
DOI: 10.1124/jpet.122.001438 -
BMC Complementary Medicine and Therapies Nov 2023Myrtus communis L. (MC) has been used in Mesopotamian medicine. Here, the cholinesterase (ChE) inhibitory potential of its methyl alcohol extracts has been investigated...
BACKGROUND
Myrtus communis L. (MC) has been used in Mesopotamian medicine. Here, the cholinesterase (ChE) inhibitory potential of its methyl alcohol extracts has been investigated and computationally dissected.
METHOD
The ChE inhibition has been measured based on usual Ellman's colorimetric method compared to a canonical ChE inhibitor, eserine. Through a deep text mining, the structures of phytocompounds (= ligands) of MC were curated from ChemSpider, PubChem, and ZINC databases and docked into protein targets, AChE (PDB 1EVE) and BChE (PDB 1P0I) after initial in silico preparedness and binding affinity (BA; kcal/mol) reported as an endpoint. The calculation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) features of phytocompounds were retrieved from SwissADME ( http://www.swissadme.ch/ ) and admetSAR software to predict the drug-likeness or lead-likeness fitness. The Toxtree v2.5.1, software platforms ( http://toxtree.sourceforge.net/ ) have been used to predict the class of toxicity of phytocompounds. The STITCH platform ( http://stitch.embl.de ) has been employed to predict ChE-chemicals interactions.
RESULTS
The possible inhibitory activities of AChE of extracts of leaves and berries were 37.33 and 70.00%, respectively as compared to that of eserine while inhibitory BChE activities of extracts of leaves and berries of MC were 19.00 and 50.67%, respectively as compared to that of eserine. Phytochemicals of MC had BA towards AChE ranging from -7.1 (carvacrol) to -9.9 (ellagic acid) kcal/mol. In this regard, alpha-bulnesene, (Z)-gamma-Bisabolene, and beta-bourbonene were top-listed low toxic binders of AChE, and (Z)-gamma-bisabolene was a more specific AChE binder. Alpha-cadinol, estragole, humulene epoxide II, (a)esculin, ellagic acid, patuletin, juniper camphor, linalyl anthranilate, and spathulenol were high class (Class III) toxic substances which among others, patuletin and alpha-cadinol were more specific AChE binders. Among intermediate class (Class II) toxic substances, beta-chamigrene was a more specific AChE binder while semimyrtucommulone and myrtucommulone A were more specific BChE binders.
CONCLUSION
In sum, the AChE binders derived from MC were categorized mostly as antiinsectants (e.g., patuletin and alpha-cardinal) due to their predicted toxic classes. It seems that structural amendment and stereoselective synthesis like adding sulphonate or sulphamate groups to these phytocompounds may make them more suitable candidates for considering in preclinical investigations of Alzheimer's disease.
Topics: Cholinesterase Inhibitors; Myrtus; Physostigmine; Myrtaceae; Fruit; Ellagic Acid; Cholinesterases
PubMed: 37990185
DOI: 10.1186/s12906-023-04241-z -
Organic Letters Apr 2022The first highly enantioselective asymmetric decarboxylative addition of β-keto acids with 3-alkenyl-oxindoles bearing an all-carbon quaternary stereocenter have been...
The first highly enantioselective asymmetric decarboxylative addition of β-keto acids with 3-alkenyl-oxindoles bearing an all-carbon quaternary stereocenter have been developed. The relevant products were acquired in 49-98% yields with 88-98% enantioselectivities in the presence of 0.04-1.0 mol % of chiral rhodium catalyst. The comprehensive practicability of this method was proven in the preparation of the key intermediate, which can be easily transformed into analogues of physovenine and physostigmine.
PubMed: 35357198
DOI: 10.1021/acs.orglett.2c00411