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Neuropharmacology Jul 2020Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and...
Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 μg, 1 μg and 2 μg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 μM, 10 μM, 30 μM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.
Topics: Anhedonia; Animals; Anxiety; Behavior, Animal; Cholinergic Agents; Cholinesterase Inhibitors; Depression; Female; Male; Muscarinic Agonists; Muscarinic Antagonists; Physostigmine; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M5; Swimming; Ventral Tegmental Area
PubMed: 32268153
DOI: 10.1016/j.neuropharm.2020.108089 -
Journal of Biomolecular Structure &... Sep 2022is an important ectoparasite of cattle, causing considerable economical losses. Resistance to chemical acaricides has stimulated the search for new antiparasitic drugs,...
is an important ectoparasite of cattle, causing considerable economical losses. Resistance to chemical acaricides has stimulated the search for new antiparasitic drugs, including natural products as an eco-friendly alternative of control. Flavonoids represent a class of natural compounds with many biological activities, such as enzyme inhibitors. Acetylcholinesterase is an essential enzyme for tick survival that stands out as an important target for the development of acaricides. This work aimed to predict this 3D structure by homology modeling and use the model to identify compound with inhibitory activity. The model of AChE1 (AChE1) was constructed using MODELLER program. The optimization and molecular dynamic investigation were performed in GROMACS program. The model developed was used, by molecular docking, to evaluate the anticholinesterase activity of flavonoids (quercetin, rutin, diosmin, naringin and hesperidin) and an acaricide synthetic (eserine). Additionally, inhibition of AChE and larval immersion tests were performed. The model of AChE1 showed to be sterically and energetically acceptable. In molecular dynamics simulations, the 3D structure remains stable with Root Mean Square Deviation = 3.58 Å and Root Mean Square Fluctuation = 1.43 Å. In molecular docking analyses, only eserine and quercetin show affinity energy to the AChE (Gridscore: -52.17 and -39.44 kcal/mol, respectively). Among the flavonoids, quercetin exhibited the best inhibition of AChE activity (15.8%) and mortality of larvae tick (30.2%). The use of and techniques has shown that quercetin showed promising anti-tick activity and structural requirements to interact with AChE1. Communicated by Ramaswamy H. Sarma.
Topics: Acaricides; Acetylcholinesterase; Animals; Cattle; Cholinesterase Inhibitors; Larva; Molecular Docking Simulation; Molecular Dynamics Simulation; Physostigmine; Quercetin; Rhipicephalus
PubMed: 33645442
DOI: 10.1080/07391102.2021.1889666 -
Journal of Critical Care Aug 2019The cholinergic anti-inflammatory pathway has been shown to be accessible by physostigmine salicylate in animal models. However, the cholinesterase inhibitor is not... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of physostigmine on recovery from septic shock following intra-abdominal infection - Results from a randomized, double-blind, placebo-controlled, monocentric pilot trial (Anticholium® per Se).
PURPOSE
The cholinergic anti-inflammatory pathway has been shown to be accessible by physostigmine salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated.
MATERIALS AND METHODS
In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The physostigmine group received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days.
RESULTS
Administration of physostigmine salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (-2.37, 95% CI: -5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability.
CONCLUSIONS
Treatment with physostigmine salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock.
TRIAL REGISTRATION
EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Critical Care; Double-Blind Method; Female; Humans; Intraabdominal Infections; Male; Middle Aged; Norepinephrine; Organ Dysfunction Scores; Patient Safety; Perioperative Period; Physostigmine; Pilot Projects; Sepsis; Shock, Septic; Sodium Chloride; Young Adult
PubMed: 31035187
DOI: 10.1016/j.jcrc.2019.04.012 -
American Journal of Therapeutics 2020
Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Combined Modality Therapy; Drug Overdose; Fat Emulsions, Intravenous; Female; Humans; Infusions, Intravenous; Middle Aged; Norepinephrine; Physostigmine; Quetiapine Fumarate; Respiration, Artificial; Shock; Status Epilepticus; Treatment Outcome
PubMed: 32769389
DOI: 10.1097/MJT.0000000000000969 -
PloS One 2022Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and...
Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17β-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17β-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 μM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17β-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17β-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.
Topics: Acetylcholinesterase; Animals; Cholinergic Agents; Entorhinal Cortex; Estradiol; Estrogens; Excitatory Postsynaptic Potentials; Female; Humans; Ovariectomy; Physostigmine; Rats; Receptor, Muscarinic M1; Synaptic Transmission; Vesicular Acetylcholine Transport Proteins
PubMed: 35939438
DOI: 10.1371/journal.pone.0271131 -
American Journal of TherapeuticsAdvances in drug therapy for myasthenia gravis have had a significant impact on the quality of life and work potential of a substantial majority of affected persons and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Advances in drug therapy for myasthenia gravis have had a significant impact on the quality of life and work potential of a substantial majority of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality.
STUDY QUESTION
What are the milestones of the changes in the expert approach to the pharmacological management of myasthenia in the past century?
STUDY DESIGN
To determine the changes in the experts' approach to the management of myasthenia gravis, as presented in a widely used textbook in the United States.
DATA SOURCES
The chapters presenting the management of myasthenia gravis in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020.
RESULTS
Adequate feeding, absolute rest in bed, and "tonics" were the only interventions recommended for the care of patients with myasthenia gravis in 1927. Ephedrine and glycine were used in the early 1930s. Treatment with the anticholinesterases physostigmine and neostigmine was recommended in 1937, 3 years after Mary Walker discovered it in the United Kingdom. Immunosuppressant pharmacological interventions with prednisone and azathioprine have been considered the standard since 1975, and intravenous immune globulin was added to usual care in 1996. The newer immunosuppressant drugs mycophenolate, cyclosporine, and tacrolimus have expanded the arsenal since 2008, and the monoclonal antibodies rituximab and eculizumab have been mentioned in the textbooks published in 2012-2020. The first randomized clinical trial of drug therapy for myasthenia gravis was published in 1987.
CONCLUSIONS
The pharmacological management of myasthenia gravis was revolutionized by the epiphany of an astute clinician in the 1930s. Immunosuppressant treatment was a logical step once the autoimmune nature of the condition was established. The major therapeutic advances highlight the values of empiricism and persistent attention to detail in treating relatively rare chronic disorders.
Topics: Expert Testimony; Humans; Myasthenia Gravis; Prednisone; Quality of Life; Rituximab
PubMed: 34757964
DOI: 10.1097/MJT.0000000000001454 -
Archives of Toxicology Mar 2023Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central...
Pretreatment of rhesus monkeys with transdermal patches containing physostigmine and procyclidine: implications of the delivery system for the potential application against VX nerve agent intoxication in humans.
Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm) containing 4.4 mg Phs and 17.8 mg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm and 49 cm patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm and 49 cm patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm patch (i.e., 22 mg Phs), and two applications of a 49 cm patch (i.e., 17.4 mg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm patch and 23.0% for the 49 cm patch) for up to 216 h, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans.
Topics: Animals; Humans; Physostigmine; Procyclidine; Nerve Agents; Macaca mulatta; Cholinesterase Inhibitors; Acetylcholinesterase; Soman
PubMed: 36633609
DOI: 10.1007/s00204-022-03438-4 -
The Journal of Pediatric Pharmacology... 2023Included on the World Health Organization Model Lists of Essential Medicines, atropine remains a cornerstone medication that is used for a myriad of clinical...
Included on the World Health Organization Model Lists of Essential Medicines, atropine remains a cornerstone medication that is used for a myriad of clinical indications. Systemically, atropine carries indications for the treatment of asymptomatic and symptomatic bradycardia, reduction of salivation and bronchial secretions prior to surgery, and as an antidote for a variety of poisoning agents (i.e., carbamate or organophosphate insecticides, nerve agents, muscarine-containing mushrooms). Topically, atropine is administered via the ophthalmic route for the treatment of cycloplegia, mydriasis, and amblyopia or may be administered sublingually to treat chronic sialorrhea. As an anticholinergic, supratherapeutic concentrations of atropine result in a toxidrome typical of other anticholinergic medication overdoses. However, it is easy to overlook atropine as the causative agent when being administered topically, potentially resulting in an unnecessarily extensive and complicated workup. This case report describes the systemic absorption of atropine administered through the ophthalmic route at normal doses, resulting in stroke-like symptoms in an adolescent male. Upon identifying that the patient was being treated with atropine ophthalmic drops prior to hospital arrival, a dose of intravenous physostigmine was administered, resulting in complete reversal of all toxidrome symptoms.
PubMed: 38130339
DOI: 10.5863/1551-6776-28.6.565 -
Chemical Communications (Cambridge,... May 2023Herein, we describe an effective strategy for enantioselective synthesis of oxindoles having a C3-quaternary stereocenter N-heterocyclic carbene (NHC) catalyzed...
Herein, we describe an effective strategy for enantioselective synthesis of oxindoles having a C3-quaternary stereocenter N-heterocyclic carbene (NHC) catalyzed desymmetrization of diols. The process is based on the catalytic asymmetric transfer acylation of primary alcohols using readily available aldehydes as an acylation agent. The reaction enables easy access to diversely functionalized C3-quaternary oxindoles with excellent enantioselectivity. The synthetic potential of the process is further demonstrated the preparation of the key intermediate for (-)-esermethole and (-)-physostigmine.
PubMed: 37096372
DOI: 10.1039/d3cc00489a -
Frontiers in Cell and Developmental... 2021Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor....
Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset ( = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and "stepAIC" algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset ( = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the "pRRophetic" and "TIDE" algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. The FRGPI was established based on the , , , and genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4 T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4 T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.
PubMed: 35174170
DOI: 10.3389/fcell.2021.812422