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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 -
Journal of Enzyme Inhibition and... Dec 2021For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer's...
For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer's disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the inhibitory concentration of 11 compounds, ranging from 14 to 985 μM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors.
Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Electrophorus; Molecular Docking Simulation; Molecular Structure; Physostigmine; Structure-Activity Relationship
PubMed: 33478277
DOI: 10.1080/14756366.2021.1876685 -
Cureus Nov 2020Physostigmine is a cholinesterase inhibitor used therapeutically in patients with anticholinergic delirium that is so severe that intubation may be required for airway...
Physostigmine is a cholinesterase inhibitor used therapeutically in patients with anticholinergic delirium that is so severe that intubation may be required for airway protection. Given that a wide variety of medications have anticholinergic properties, and the current standard of care is typically a central nervous system depressant, hospitalizations are often lengthy and normally require a critical-care level of attention. Despite this, physostigmine is often underutilized and poorly understood in the clinical setting. We report a case of a 43-year-old female who presented to the emergency department one hour after ingesting approximately 150 tablets of diphenhydramine in a suicide attempt. She was treated with benzodiazepines with minimal success, and airway protection became imminent as her mentation continued to decline. Through the use of physostigmine, we were able to save this patient from endotracheal intubation and the potential complications of mechanical ventilation.
PubMed: 33403170
DOI: 10.7759/cureus.11739 -
Biomolecules Dec 2020In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its...
In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (M). We hereby used two approaches based on molecular docking simulation to explore the interaction of four libraries of semisynthetic nitrogenous heterocyclic compounds with M. Libraries L1 and L2 contain 52 synthetic derivatives of the natural compound 2-propylquinoline, whereas libraries L3 and L4 contain 65 compounds synthesized using the natural compound physostigmine as a precursor. Validation through redocking suggested that the rigid receptor and flexible receptor approaches used for docking were suitable to model the interaction of this type of compounds with the target protein, although the flexible approach seemed to provide a more realistic representation of interactions within the active site. Using empirical energy score thresholds, we selected 58 compounds from the four libraries with the most favorable energy estimates. Globally, favorable estimates were obtained for molecules with two or more substituents, putatively accommodating in three or more subsites within the M active site. Our results pave the way for further experimental evaluation of the selected compounds as potential antiviral agents against SARS-CoV-2.
Topics: Antiviral Agents; COVID-19; Catalytic Domain; Coronavirus 3C Proteases; Heterocyclic Compounds; Humans; Molecular Dynamics Simulation; Pandemics; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33375460
DOI: 10.3390/biom11010018 -
Journal of Experimental & Clinical... Dec 2020Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated...
BACKGROUND
Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine.
METHODS
We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival.
RESULTS
We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves.
CONCLUSION
For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.
Topics: Acetylcholine; Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Cell Cycle; Cell Movement; Cell Proliferation; Choline O-Acetyltransferase; Cholinergic Agents; Female; Humans; Inflammation; Male; Mice; Middle Aged; Neoplasm Invasiveness; Pancreatic Neoplasms; Prognosis; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33357230
DOI: 10.1186/s13046-020-01796-4 -
British Journal of Anaesthesia Mar 2021Several studies have shown that cholinergic mechanisms play a pivotal role in the anti-nociceptive system by acting synergistically with morphine and reducing... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Several studies have shown that cholinergic mechanisms play a pivotal role in the anti-nociceptive system by acting synergistically with morphine and reducing postoperative opioid consumption. In addition, the anti-cholinesterase drug physostigmine that increases synaptic acetylcholine concentrations has anti-inflammatory effects.
METHODS
In this randomised placebo-controlled trial including 110 patients undergoing nephrectomy, we evaluated the effects of intraoperative physostigmine 0.5 mg h i.v. for 24 h on opioid consumption, hyperalgesia, pain scores, and satisfaction with pain control.
RESULTS
Physostigmine infusion did not affect opioid consumption compared with placebo. However, the mechanical pain threshold was significantly higher (2.3 [sd 0.3]) vs 2.2 [0.4]; P=0.0491), and the distance from the suture line of hyperalgesia (5.9 [3.3] vs 8.5 [4.6]; P=0.006), wind-up ratios (2.2 [1.5] vs 3.1 [1.5]; P=0.0389), and minimum and maximum postoperative pain scores at 24 h (minimum 1.8 [1.0] vs 2.4 [1.2]; P=0.0451; and maximum 3.2 [1.4] vs 4.2 [1.4]; P=0.0081) and 48 h (minimum 0.9 [1.0] vs 1.6 [1.1]; P=0.0101; and maximum 2.0 [1.5] vs 3.2 [1.6]; P=0.0029) were lower in the study group. Pain Disability Index was lower and satisfaction with pain control was higher after 3 months in the physostigmine group.
CONCLUSIONS
In contrast to previous trials, physostigmine did not reduce opioid consumption. As pain thresholds were higher and hyperalgesia and wind-up lower in the physostigmine group, we conclude that physostigmine has anti-hyperalgesic effects and attenuates sensitisation processes. Intraoperative physostigmine may be a useful and safe addition to conventional postoperative pain control.
CLINICAL TRIAL REGISTRATION
EudraCT number 2012-000130-19.
Topics: Analgesics, Opioid; Anesthesia, General; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Female; Humans; Hyperalgesia; Male; Middle Aged; Morphine; Nephrectomy; Pain, Postoperative; Perioperative Care; Physostigmine; Prospective Studies
PubMed: 33317802
DOI: 10.1016/j.bja.2020.10.039 -
Translational Psychiatry Nov 2020Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later...
Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice.
Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.
Topics: Animals; Bipolar Disorder; Depression; Kidney Diseases; Mice; Mutation; Receptor, trkA
PubMed: 33235206
DOI: 10.1038/s41398-020-01087-8 -
Alzheimer's & Dementia : the Journal of... Feb 2021Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis...
OBJECTIVE
Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments.
BACKGROUND
AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein-coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C-terminal fragment (C99, also known as β-CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals.
NEW/UPDATED HYPOTHESIS
We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full-length APP (fl-APP) and its products, including β-CTF and possibly Aβ peptides (Aβ42 and Aβ40), drive AD pathogenesis through an endosome-dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl-APP. In vitro, Posiphen lowered fl-APP and its C-terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl-APP, C-terminal fragments and small reductions in Aβ species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p-tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal-regulated kinase), and CREB (cAMP response element-binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS.
MAJOR CHALLENGES FOR THE HYPOTHESIS
Important unanswered questions are: (1) When should one intervene in those with DS; (2) would an APP-based strategy have untoward consequences on possible adaptive changes induced by chronically increased APP gene dose; (3) do other genes present on chromosome 21, or on other chromosomes whose expression is dysregulated in DS, contribute to AD pathogenesis; and (4) can one model strategies that combine the use of an APP-based treatment with those directed at other AD phenotypes including p-tau and inflammation.
LINKAGE TO OTHER MAJOR THEORIES
The APP gene dose hypothesis interfaces with the amyloid cascade hypothesis of AD as well as with the genetic and cell biological observations that support it. Moreover, upregulation of fl-APP protein and products may drive downstream events that dysregulate tau homeostasis and inflammatory responses that contribute to propagation of AD pathogenesis.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Down Syndrome; Endosomes; Humans; Mice; Neurons; Phenotype; Phosphorylation; Physostigmine
PubMed: 32975365
DOI: 10.1002/alz.12185 -
Cognitive, Affective & Behavioral... Dec 2020Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising...
Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising during short active (SA) winter periods. Light-induced changes in behavior are also seen in healthy animals and are intensified in mice with reduced dopamine transporter expression. Specifically, decreasing the nocturnal active period (SA) of mice increases punishment perseveration and forced swim test (FST) immobility. Elevating acetylcholine with the acetylcholinesterase inhibitor physostigmine induces depression symptoms in people and increases FST immobility in mice. We used SA photoperiods and physostigmine to elevate acetylcholine prior to testing in a probabilistic learning task and the FST, including reversing subsequent deficits with nicotinic and scopolamine antagonists and targeted hippocampal adeno-associated viral administration. We confirmed that physostigmine also increases punishment sensitivity in a probabilistic learning paradigm. In addition, muscarinic and nicotinic receptor blockade attenuated both physostigmine-induced and SA-induced phenotypes. Finally, viral-mediated hippocampal expression of human AChE used to lower ACh levels blocked SA-induced elevation of FST immobility. These results indicate that increased hippocampal acetylcholine neurotransmission is necessary for the expression of SA exposure-induced behaviors. Furthermore, these studies support the potential for cholinergic treatments in depression. Taken together, these results provide evidence for hippocampal cholinergic mechanisms in contributing to seasonally depressed affective states induced by short day lengths.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Hippocampus; Mice; Photoperiod; Physostigmine
PubMed: 32794101
DOI: 10.3758/s13415-020-00824-2