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Assessment of anti-cholinesterase activity and cytotoxicity of cagaita (Eugenia dysenterica) leaves.Food and Chemical Toxicology : An... Nov 2017Eugenia dysenterica ex DC Mart. (Myrtaceae) is a Brazilian tree with pharmacological and biological properties. The aqueous leaf extract, rich in polyphenols, was tested...
Eugenia dysenterica ex DC Mart. (Myrtaceae) is a Brazilian tree with pharmacological and biological properties. The aqueous leaf extract, rich in polyphenols, was tested in the human neuroblastoma cell line SH-SY5Y to evaluate its effect on cell viability. The extract and two isolated compounds were also assessed for the potential inhibitory activity on acetylcholinesterase, an enzyme related to Alzheimer's disease. A simple chromatographic method using Sephadex LH-20 was developed to separate catechin and quercetin from the aqueous leaf extract of E. dysenterica. Identification was carried out by spectroscopic techniques IR, UV, and H and C NMR. The IC values were obtained by constructing dose-response curves on a graph with percentage inhibition versus log of inhibitor concentration and compared with physostigmine, a well-known AChE inhibitor. The extract was toxic for SH-SY5Y cells at concentrations higher than 7.8 μg/ml given for 24 h. The decline in SH-SY5Y cell viability appears to be related to its antiproliferative activity. The extract also showed relatively moderate acetylcholinesterase inhibitory activity of 66.33% ± 0.52% at 1.0 mg/ml with an IC value of 155.20 ± 2.09 μg/ml. Physostigmine, quercetin, and catechin showed IC values of 18.69 ± 0.07, 46.59 ± 0.49, and 42.39 ± 0.67 μg/ml, respectively.
Topics: Brazil; Cell Line; Cell Survival; Cholinesterase Inhibitors; Cholinesterases; Eugenia; Humans; Kinetics; Phenols; Plant Extracts; Plant Leaves
PubMed: 28238772
DOI: 10.1016/j.fct.2017.02.032 -
Journal of Biomolecular Structure &... Dec 2023Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses... (Review)
Review
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses due to other unaltered physiological factors. The solution for this problem is Multi-targeted Drugs (MTDs), which can affect multiple determinants to realize the multifunctional effects. Acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist memantine are FDA-approved drugs used to treat AD symptomatically. The key objective of this review is to understand multitargeted bioactive natural molecules that could be considered as leads for further development as effective drugs for treating AD, along with understanding its pharmacology and structure-activity relationship (SAR). Understanding the molecular mechanism of the AD pathophysiology, the role of existing drugs, treatment of AD via amyloid beta (Aβ) plaque, and neurofibrillary tangle (NFT) inhibition by natural bioactive molecules were also discussed in the review. The current quest and recent advancements with natural bioactive compounds like physostigmine, resveratrol, curcumin, and catechins, along with the study of SAR, were reported in the present study. This review summarises the structural properties required for bioactive natural molecules to show anti-Alzheimer's activity by emphasizing on SAR of several bioactive natural molecules targeting various AD pathologies, their key molecular interactions that are critical for target specificity, their role as multitargeted ligands, used with adjunctive therapy for AD followed by related US patents granted recently. This article highlights the significance of the structural features of natural bioactive molecules in the treatment of AD and establishes a connection between them.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Acetylcholinesterase; Cholinesterase Inhibitors; Structure-Activity Relationship
PubMed: 36579430
DOI: 10.1080/07391102.2022.2158136 -
Expert Opinion on Therapeutic Patents Apr 2017Acetylcholinesterase (AChE) is the major enzyme that hydrolyzes acetylcholine, a key neurotransmitter for synaptic transmission, into acetic acid and choline. Mild... (Review)
Review
Acetylcholinesterase (AChE) is the major enzyme that hydrolyzes acetylcholine, a key neurotransmitter for synaptic transmission, into acetic acid and choline. Mild inhibition of AChE has been shown to have therapeutic relevance in Alzheimer's disease (AD), myasthenia gravis, and glaucoma among others. In contrast, strong inhibition of AChE can lead to cholinergic poisoning. To combat this, AChE reactivators have to be developed to remove the offending AChE inhibitor, restoring acetylcholine levels to normal. Areas covered: This article covers recent advances in the development of acetylcholinesterase modulators, including both inhibitors of acetylcholinesterase for the efforts in development of new chemical entities for treatment of AD, as well as re-activators for resurrection of organophosphate bound acetylcholinesterase. Expert opinion: Over the past three years, research efforts have continued to identify novel small molecules as AChE inhibitors for both CNS and peripheral diseases. The more recent patent activity has focused on three AChE ligand design areas: derivatives of known AChE ligands, natural product based scaffolds and multifunctional ligands, all of which have produced some unique chemical matter with AChE inhibition activities in the mid picomolar to low micromolar ranges. New AChE inhibitors with polypharmacology or dual inhibitory activity have also emerged as highlighted by new AChE inhibitors with dual activity at L-type calcium channels, GSK-3, BACE1 and H3, although most only show low micromolar activity, thus further research is warranted. New small molecule reactivators of organophosphate-inhibited AChE have also been disclosed, which focused on the design of neutral ligands with improved pharmaceutical properties and blood-brain barrier (BBB) penetration. Gratifyingly, some research in this area is moving away from the traditional quaternary pyridinium oximes AChE reactivators, while still employing the necessary reactivation group (oximes). However, selectivity over inhibition of native AChE enzyme, effectiveness of reactivation, broad-spectrum reactivation against multiple organophosphates and reactivation of aged-enzyme continue to be hurdles for this area of research.
Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Drug Design; Glaucoma; Humans; Ligands; Myasthenia Gravis; Patents as Topic
PubMed: 27967267
DOI: 10.1080/13543776.2017.1272571 -
Journal of Pineal Research Aug 2023Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes...
Arylacetamide deacetylase (AADAC) is a deacetylation enzyme present in the mammalian liver, gastrointestinal tract, and brain. During our search for mammalian enzymes capable of metabolizing N-acetylserotonin (NAS), AADAC was identified as having the ability to convert NAS to serotonin. Both human and rodent recombinant AADAC proteins can deacetylate NAS in vitro, although the human AADAC shows markedly higher activity compared with rodent enzyme. The AADAC-mediated deacetylation reaction can be potently inhibited by eserine in vitro. In addition to NAS, recombinant hAADAC can deacetylate melatonin (to form 5-methoxytryptamine) and N-acetyltryptamine (NAT) (to form tryptamine). In addition to the in vitro deacetylation of NAS by the recombinant AADAC proteins, liver (mouse and human) and brain (human) extracts were able to deacetylate NAS; these activities were sensitive to eserine. Taken together, these results demonstrate a new role for AADAC and suggest a novel pathway for the AADAC-mediated metabolism of pineal indoles in mammals.
Topics: Animals; Humans; Mice; Carboxylic Ester Hydrolases; Mammals; Melatonin; Physostigmine; Serotonin
PubMed: 37002641
DOI: 10.1111/jpi.12870 -
British Journal of Clinical Pharmacology Nov 2021HTL0009936 is a selective M muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
HTL0009936 is a selective M muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF).
METHODS
Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests.
RESULTS
Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine.
CONCLUSIONS
HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.
Topics: Aged; Area Under Curve; Cholinergic Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Receptors, Cholinergic
PubMed: 33891333
DOI: 10.1111/bcp.14872 -
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 -
Neurological Research May 2016Surgical interventions can cause systemic postoperative inflammation, which in turn can induce neuroinflammation. A close link between immune reaction and cholinergic...
OBJECTIVES
Surgical interventions can cause systemic postoperative inflammation, which in turn can induce neuroinflammation. A close link between immune reaction and cholinergic metabolism has been postulated. Pharmacological enhancement of cholinergic activity by administering physostigmine is known to induce protective effects. It is not known, however, whether physostigmine has an impact on postoperative inflammation and acetylcholine metabolism after a partial liver resection (PLR) surgery.
METHODS
Rats (n = 100) underwent a PLR or sham surgery. Rats were investigated before the intervention and 120 min and 24 h postoperatively. The control group only received sevoflurane anaesthesia. Half of each treatment group received a single intraoperative dose of physostigmine, whereas the others were given placebo. Acetylcholine (ACHE) and butyrylcholinesterase (BuCHE) activity and IL1β, IL6 and corticosterone levels were measured in rat plasma and brain. Acetylcholine (ACH) concentrations were determined additionally in cerebral tissue.
RESULTS
Surgical interventions induced a peripheral stress reaction, which was characterized by an increase (p < 0.05) in pro-inflammatory cytokines, cholinergic esterases and corticosterone at 120 min postoperatively in rat blood and in cerebral tissue. At 24 h postoperatively, all measured cerebral parameters reached control values. In blood, IL1β and BuCHE were still increased, suggesting they are peripheral markers of a stress reaction. The reduced cerebral acetylcholine is increased after physostigmine administration. Furthermore, physostigmine reduced IL1β (p < 0.05).
CONCLUSION
We show in this observational study that a single intraoperative dose of physostigmine produced a sustained anti-inflammatory effect in rat blood and brain up to 120 min postoperatively, which was especially pronounced under the condition of PLR surgery.
Topics: Acetylcholine; Anesthesia; Animals; Cholinesterase Inhibitors; Cholinesterases; Corticosterone; Cytokines; Disease Models, Animal; Encephalitis; Liver; Male; Physostigmine; Postoperative Complications; Rats; Rats, Wistar; Statistics, Nonparametric; Stress, Psychological
PubMed: 27095151
DOI: 10.1080/01616412.2016.1173889 -
Behavioural Pharmacology Aug 2016The effects on tramadol state-dependent memory of bilateral intradorsal hippocampal (intra-CA1) injections of physostigmine, an acetylcholinesterase inhibitor, and...
The effects on tramadol state-dependent memory of bilateral intradorsal hippocampal (intra-CA1) injections of physostigmine, an acetylcholinesterase inhibitor, and atropine, a muscarinic acetylcholine receptor antagonist, were examined in adult male NMRI mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention. Post-training intra-CA1 administration of an atypical μ-opioid receptor agonist, tramadol (0.5 and 1 μg/mouse), dose dependently impaired memory retention. Pretest injection of tramadol (0.5 and 1 μg/mouse, intra-CA1) induced state-dependent retrieval of the memory acquired under the influence of post-training tramadol (1 μg/mouse, intra-CA1). A pretest intra-CA1 injection of physostigmine (1 μg/mouse) reversed the memory impairment induced by post-training administration of tramadol (1 μg/mouse, intra-CA1). Moreover, pretest administration of physostigmine (0.5 and 1 μg/mouse, intra-CA1) with an ineffective dose of tramadol (0.25 μg/mouse, intra-CA1) also significantly restored retrieval. Pretest administration of physostigmine (0.25, 0.5, and 1 μg/mouse, intra-CA1) by itself did not affect memory retention. A pretest intra-CA1 injection of the atropine (1 and 2 μg/mouse) 5 min before the administration of tramadol (1 μg/mouse, intra-CA1) dose dependently inhibited tramadol state-dependent memory. Pretest administration of atropine (0.5, 1, and 2 μg/mouse, intra-CA1) by itself did not affect memory retention. It can be concluded that dorsal hippocampal muscarinic acetylcholine receptor mechanisms play an important role in the modulation of tramadol state-dependent memory.
Topics: Analgesics, Opioid; Animals; Atropine; Avoidance Learning; CA1 Region, Hippocampal; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Hippocampus; Male; Memory; Mice; Muscarinic Antagonists; Physostigmine; Receptors, Muscarinic; Tramadol
PubMed: 27089282
DOI: 10.1097/FBP.0000000000000239 -
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