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The Journal of Physiology Feb 2017This study investigates the effects of cholinergic transmission on the expiratory oscillator, the parafacial respiratory group (pFRG) in urethane anaesthetized adult...
KEY POINTS
This study investigates the effects of cholinergic transmission on the expiratory oscillator, the parafacial respiratory group (pFRG) in urethane anaesthetized adult rats. Local inhibition of the acetyl cholinesterase enzyme induced activation of expiratory abdominal muscles and active expiration. Local application of the cholinomimetic carbachol elicited recruitment of late expiratory neurons, expiratory abdominal muscle activity and active expiration. This effect was antagonized by local application of the muscarinic antagonists scopolamine, J104129 and 4DAMP. We observed distinct physiological responses between the more medial chemosensitive region of the retrotrapezoid nucleus and the more lateral region of pFRG. These results support the hypothesis that pFRG is under cholinergic neuromodulation and the region surrounding the facial nucleus contains a group of neurons with distinct physiological roles.
ABSTRACT
Active inspiration and expiration are opposing respiratory phases generated by two separate oscillators in the brainstem: inspiration driven by a neuronal network located in the preBötzinger complex (preBötC) and expiration driven by a neuronal network located in the parafacial respiratory group (pFRG). While continuous activity of the preBötC is necessary for maintaining ventilation, the pFRG behaves as a conditional expiratory oscillator, being silent in resting conditions and becoming rhythmically active in the presence of increased respiratory drive (e.g. hypoxia, hypercapnia, exercise and through release of inhibition). Recent evidence from our laboratory suggests that expiratory activity in the principal expiratory pump muscles, the abdominals, is modulated in a state-dependent fashion, frequently occurring during periods of REM sleep. We hypothesized that acetylcholine, a neurotransmitter released in wakefulness and REM sleep by mesopontine structures, contributes to the activation of pFRG neurons and thus acts to promote the recruitment of expiratory abdominal muscle activity. We investigated the stimulatory effect of cholinergic neurotransmission on pFRG activity and recruitment of active expiration in vivo under anaesthesia. We demonstrate that local application of the acetylcholinesterase inhibitor physostigmine into the pFRG potentiated expiratory activity. Furthermore, local application of the cholinomimetic carbachol into the pFRG activated late expiratory neurons and induced long lasting rhythmic active expiration. This effect was completely abolished by pre-application of the muscarinic antagonist scopolamine, and more selective M3 antagonists 4DAMP and J104129. We conclude that cholinergic muscarinic transmission contributes to excitation of pFRG neurons and promotes both active recruitment of abdominal muscles and active expiratory flow.
Topics: Animals; Brain Stem; Cholinergic Agonists; Cholinergic Antagonists; Cholinesterase Inhibitors; Male; Muscarinic Antagonists; Neurons; Rats; Rats, Sprague-Dawley; Respiration; Sleep, REM; Wakefulness
PubMed: 27808424
DOI: 10.1113/JP273012 -
Biomedicine & Pharmacotherapy =... Jan 2018Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to... (Comparative Study)
Comparative Study
Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to study the effect of boldine on the learning and memory of the Swiss albino male young and aged mice. Boldine (1.5, 3 and 6mg/kg, po) and physostigmine salicylate (0.1mg/kg, ip) were administered to separate groups of mice for 7 successive days. Morris water maze was utilized as a behavioural model to study the effect of drugs on learning and memory of mice. Boldine and physostigmine significantly improved learning and memory of young as well as aged mice, as indicated by decrease in escape latency time during training session and increase in time spent in target quadrant during retrieval session. No significant effect on locomotor activities of mice was observed due to drug treatments. Memory-enhancing activity of boldine (3mg/kg) was found to be comparable to physostigmine. Boldine significantly reversed scopolamine-, sodium nitrite- and aging-induced amnesia in mice. Moreover, boldine attenuated oxidative stress, as shown by a significant decrease in brain malondialdehyde as well as brain nitrite levels and a significant increase in brain GSH level of young as well as aged mice. Brain acetylcholinesterase activity was also significantly inhibited by boldine in young as well as aged mice. In conclusion boldine administered for 7 successive days exhibited significant improvement of learning and memory of young and aged mice possibly through inhibition of brain acetylcholinesterase activity and alleviation of brain oxidative stress.
Topics: Acetylcholinesterase; Age Factors; Amnesia; Animals; Aporphines; Behavior, Animal; Brain; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Glutathione; Male; Malondialdehyde; Maze Learning; Memory; Mice; Nitrites; Nootropic Agents; Oxidative Stress; Physostigmine
PubMed: 29136766
DOI: 10.1016/j.biopha.2017.11.011 -
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 -
Journal of Biomedical Science Sep 2017Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults of less than 45 years of age and the elderly, and... (Review)
Review
Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults of less than 45 years of age and the elderly, and contributes to about 30% of all injury deaths in the United States of America. Whereas there has been a significant improvement in our understanding of the mechanism that underpin the primary and secondary stages of damage associated with a TBI incident, to date however, this knowledge has not translated into the development of effective new pharmacological TBI treatment strategies. Prior experimental and clinical studies of drugs working via a single mechanism only may have failed to address the full range of pathologies that lead to the neuronal loss and cognitive impairment evident in TBI and other disorders. The present review focuses on two drugs with the potential to benefit multiple pathways considered important in TBI. Notably, both agents have already been developed into human studies for other conditions, and thus have the potential to be rapidly repositioned as TBI therapies. The first is N-acetyl cysteine (NAC) that is currently used in over the counter medications for its anti-inflammatory properties. The second is (-)-phenserine ((-)-Phen) that was originally developed as an experimental Alzheimer's disease (AD) drug. We briefly review background information about TBI and subsequently review literature suggesting that NAC and (-)-Phen may be useful therapeutic approaches for TBI, for which there are no currently approved drugs.
Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Brain Injuries, Traumatic; Cholinesterase Inhibitors; Drug Repositioning; Humans; Mice; Physostigmine; Psychotropic Drugs; Rats
PubMed: 28886718
DOI: 10.1186/s12929-017-0377-1 -
Critical Care Clinics Jul 2017The most important diagnostic factor in uncovering a toxic etiology for delirium or critical illness is the clinician's openness to the possibility of its existence.... (Review)
Review
The most important diagnostic factor in uncovering a toxic etiology for delirium or critical illness is the clinician's openness to the possibility of its existence. Therefore, a consulting psychiatrist, already prepared to perform the detail-oriented work of sorting out behavioral manifestations of disease, can be a vital asset at the bedside if also attuned to the role of purposeful, accidental, and iatrogenic exposures in the intensive care unit. This article summarizes the presentation, evaluation, and treatment of toxidromes relevant to the work of acute psychosomatic medicine.
Topics: Critical Care; Critical Illness; Delirium; Humans; Intensive Care Units; Physician's Role; Poisoning; Psychiatry
PubMed: 28601133
DOI: 10.1016/j.ccc.2017.03.002 -
Neuropsychopharmacology : Official... Mar 2023The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few...
The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β-subunit containing nicotinic acetylcholine receptor (β*-nAChR) partial agonist radioligand (-)-[F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (V) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[F]flubatine V, consistent with increased cortical acetylcholine levels reducing the number of β*-nAChR sites available for (-)-[F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[F]flubatine V was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
Topics: Animals; Male; Female; Acetylcholine; Acetylcholinesterase; Physostigmine; Positron-Emission Tomography; Brain; Receptors, Nicotinic; Cognition; Cholinergic Agents; Smoking
PubMed: 36681758
DOI: 10.1038/s41386-023-01535-1 -
The Journal of Surgical Research Apr 2015Recently, protection in shock (hemorrhagic or septic) by physostigmine has been demonstrated. Here, we studied the protective effect of intravenous infusion of...
BACKGROUND
Recently, protection in shock (hemorrhagic or septic) by physostigmine has been demonstrated. Here, we studied the protective effect of intravenous infusion of physostigmine in a rat model of severe intestinal ischemia-reperfusion (I/R) injury and shock.
MATERIALS AND METHODS
Mesenteric I/R was induced in male Wistar rats by occlusion of the superior mesenteric artery (90 min) and subsequent reperfusion (120 min). Physostigmine (30 or 70 μg/kg) was administered as bolus injection before induction of I/R. One additional group received, subsequent to the bolus of 30-μg/kg physostigmine, a continuous infusion of 60-μg/kg physostigmine till the end of the experiment.
RESULTS
Physostigmine at a dose of 70 μg/kg administered before I/R significantly decreased the macroscopically and microscopically visible intestinal damage. In addition to and presumably as a result of this local protective effect, physostigmine prevented shock induced by reperfusion of the ischemically injured intestine. Lower doses (30 μg/kg) or continuous application of physostigmine were less advantageous.
CONCLUSIONS
Physostigmine is clearly protective in intestinal I/R injury and shock. However, for this purpose, physostigmine has to be applied at a dose (70 μg/kg), that is, approximately double the amount of the presently used clinical dose.
Topics: Administration, Intravenous; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Intestine, Small; Male; Mesenteric Artery, Superior; Physostigmine; Rats, Wistar; Reperfusion Injury; Shock
PubMed: 25483738
DOI: 10.1016/j.jss.2014.11.003 -
Neuropsychopharmacology : Official... Aug 2022The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and...
The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.
Topics: Acetylcholinesterase; Bipolar Disorder; Case-Control Studies; Cholinergic Agents; Emotions; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Physostigmine; Synaptic Transmission
PubMed: 35046509
DOI: 10.1038/s41386-022-01268-7 -
Journal of Ethnopharmacology Apr 2018Alzheimer's disease (AD), a deleterious neurodegenerative disorder that impairs memory, cognitive functions and may lead to dementia in late stage of life. The... (Review)
Review
ETHNOPHARMACOLOGICAL RELEVANCE
Alzheimer's disease (AD), a deleterious neurodegenerative disorder that impairs memory, cognitive functions and may lead to dementia in late stage of life. The pathogenic cause of AD remains incompletely understood and FDA approved drugs are partial inhibitors rather than curative. Most of drugs are synthetic or natural products as galanthamine is an alkaloid obtained from Galanthus spp. Huperzine A, an alkaloid found in Huperzia spp., gingkolides a diterpenoids from Gingko biloba and many ethnobotanicals like Withania somnifera (L.) Dunal., Physostigma venenosum Balf., Bacopa monnieri (L.) Wettst., Centella asiatica (L.) Urb. have been used by traditional Indian, Chinese, and European system of medicines in AD. Clinical significance opioid alkaloid in Papaver somniferum has shown another dimension to this study. Over exploitation of medicinal plants with limited bioactive principles has provided templates to design synthetic drugs in AD e.g. rivastigmine, phenserine, eptastigmine based on chemical structure of physostigmine of Physostigma venenosum Balf. Even ZT-1 a prodrug of Hup A and memogain a prodrug of galantamine has achieved new direction in drug development in AD. All these first-line cholinesterase-inhibitors are used as symptomatic treatments in AD. Single modality of "One-molecule-one-target" strategy for treating AD has failed and so future therapies on "Combination-drugs-multi-targets" strategy (CDMT) will need to address multiple aspects to block the progression of pathogenesis of AD. Besides, cholinergic and amyloid drugs, in this article we summarize proteinopathy-based drugs as AD therapeutics from a variety of biological sources. In this review, an attempt has been made to elucidate the molecular mode of action of various plant products, and synthetic drugs investigated in various preclinical and clinical tests in AD. It also discusses current attempts to formulate a comprehensive CDMT strategy to counter complex pathogenesis in AD.
MATERIALS AND METHODS
Information were collected from classical books on medicinal plants, pharmacopoeias and scientific databases like PubMed, Scopus, GoogleScholar, Web of Science and electronic searches were performed using Cochrane Library, Medline and EMBASE. Also published scientific literatures from Elsevier, Taylor and Francis, Springer, ACS, Wiley publishers and reports by government bodies and documentations were assessed.
RESULTS
60 no. of natural and synthetic drugs have been studied with their significant bioactivities. A decision matrix designed for evaluation of drugs for considering to the hypothetic "CDMT" strategy in AD. We have introduced the scoring pattern of individual drugs and based on scoring pattern, drugs that fall within the scoring range of 18-25 are considered in the proposed CDMT. It also highlights the importance of available natural products and in future those drugs may be considered in CDMT along with the qualified synthetic drugs.
CONCLUSION
A successful validation of the CDMT strategy may open up a debate on health care reform to explore other possibilities of combination therapy. In doing so, it should focus on clinical and molecular relationships between AD and CDMT. A better understanding of these relationships could inform and impact future development of AD-directed treatment strategies. This strategy also involves in reducing costs in treatment phases which will be affordable to a common man suffering from AD.
Topics: Alzheimer Disease; Biological Products; Drug Therapy, Combination; Humans; Phytotherapy; Plant Extracts
PubMed: 29248451
DOI: 10.1016/j.jep.2017.12.015 -
Combinatorial Chemistry & High... 2022Alzheimer's disease is a destructive nervous system disease which causes structural, biochemical and electrical abnormalities inside the human brain and results due to...
BACKGROUND
Alzheimer's disease is a destructive nervous system disease which causes structural, biochemical and electrical abnormalities inside the human brain and results due to genetic and various environmental factors. Traditional therapeutic agents of Alzheimer's disease such as tacrine and physostigmine have been found to cause adverse effects to the nervous system and gastrointestinal tract. Nanomaterials like graphene, metals, carbon-nanotubes and metal-oxides are gaining attention as potential drugs against Alzheimer's disease due to their properties such as large surface area, which provide clinical efficiency, targeted drug designing and delivery.
OBJECTIVES
Designing new drugs by using experimental approaches is a time-consuming, tedious and laborious process which also requires advanced technologies. This study aims to identify some novel drug candidates against Alzheimer's disease with no or less associated side effects using molecular docking approaches Methods: In this study, we utilized nanoinformatics based approaches for evaluating the interaction properties of various nanomaterials and metal nanoparticles with the drug targets, including TRKB kinase domain, EphA4 and histone deacetylase. Furthermore, the drug-likeness of carbon nanotubes was confirmed through ADME analysis.
RESULTS
Carbon nanotubes, either single or double-walled in all the three-configurations, including zigzag, chiral, and armchair forms, are found to interact with the target receptors with varying affinities Conclusion: This study provides novel and clearer insights into the interaction properties and drug suitability of known putative nanoparticles as potential agents for the treatment of Alzheimer's disease.
Topics: Alzheimer Disease; Humans; Molecular Docking Simulation; Nanoparticles; Nanotubes, Carbon; Tacrine
PubMed: 33596794
DOI: 10.2174/1386207324666210217145733