[Poisoning with Jimson weed. Five cases treated with physostigmine].

PubMed

Amlo, H; Haugeng, K L; Wickstrøm, E; Koss, A; Husebye, T; Jacobsen, D

1997-08-10

During the autumn of 1995, the National Poisons Information Centre was contacted about several cases of poisoning with Jimson weed (Datura stramonium). Five cases are described here. Upon admission to hospital the patients had moderate to severe anticholinergic symptoms, such as mydriasis, sinus tachycardia, agitation, dry mouth, urine retention, fever, hypertension, hallucinations and seizures. Owing to their agitated behaviour, gastrointestinal decontamination was impossible. Repeated doses of physostigmine (2-3 mg) administered intravenously reversed the anticholinergic features without side-effects. In the most severe case, physostigmine was needed for 18 hours (total dose; 25.5 mg). The patients recovered in a day or two, but mydriasis persisted in many cases.

Cholinergic modulation of visual and attentional brain responses in Alzheimer's disease and in health

PubMed Central

Bentley, P.; Driver, J.; Dolan, R.J.

2008-01-01

Visuo-attentional deficits occur early in Alzheimer's disease (AD) and are considered more responsive to pro-cholinergic therapy than characteristic memory disturbances. We hypothesised that neural responses in AD during visual attentional processing would be impaired relative to controls, yet partially susceptible to improvement with cholinesterase inhibition. We studied 16 mild AD patients and 17 age-matched healthy controls, using fMRI-scanning to enable within-subject placebo-controlled comparisons of the effects of physostigmine on stimulus- and attention-related brain activations, and to allow between-group comparisons for these. Subjects viewed stimuli comprising faces or buildings while performing a shallow judgement (colour of image) or a deep judgement (young/old age of depicted face or building). Behaviourally, AD subjects performed poorer than controls in both tasks, while physostigmine benefited AD patients for the more demanding age-judgement task. Stimulus-selective (face minus building, and vice versa) BOLD signals in precuneus and posterior parahippocampal cortex were attenuated in AD relative to controls but increased following physostigmine. By contrast, face-selective responses in fusiform cortex were not impaired in AD and showed decreases following physostigmine for both groups. Task-dependent responses in right parietal and prefrontal cortices were diminished in AD but improved following physostigmine. A similar pattern of group and treatment effects was observed in two extrastriate cortical regions that showed enhanced stimulus-selectivity for the deep versus shallow task. Finally, for the healthy group, physostigmine decreased task-dependent effects, partly due to an exaggeration of selectivity during the shallow relative to deep task. Our results demonstrate cholinergic-mediated improvements for both stimulus- and attention-dependent responses in functionally affected extrastriate and frontoparietal regions for AD. We also show that normal stimulus- and task-dependent activity patterns can be perturbed in the healthy brain by cholinergic stimulation. PMID:18077465

Cholinergic enhancement modulates neural correlates of selective attention and emotional processing.

PubMed

Bentley, Paul; Vuilleumier, Patrik; Thiel, Christiane M; Driver, Jon; Dolan, Raymond J

2003-09-01

Neocortical cholinergic afferents are proposed to influence both selective attention and emotional processing. In a study of healthy adults we used event-related fMRI while orthogonally manipulating attention and emotionality to examine regions showing effects of cholinergic modulation by the anticholinesterase physostigmine. Either face or house pictures appeared at task-relevant locations, with the alternative picture type at irrelevant locations. Faces had either neutral or fearful expressions. Physostigmine increased relative activity within the anterior fusiform gyrus for faces at attended, versus unattended, locations, but decreased relative activity within the posterolateral occipital cortex for houses in attended, versus unattended, locations. A similar pattern of regional differences in the effect of physostigmine on cue-evoked responses was also present in the absence of stimuli. Cholinergic enhancement augmented the relative neuronal response within the middle fusiform gyrus to fearful faces, whether at attended or unattended locations. By contrast, physostigmine influenced responses in the orbitofrontal, intraparietal and cingulate cortices to fearful faces when faces occupied task-irrelevant locations. These findings suggest that acetylcholine may modulate both selective attention and emotional processes through independent, region-specific effects within the extrastriate cortex. Furthermore, cholinergic inputs to the frontoparietal cortex may influence the allocation of attention to emotional information.

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

PubMed

Manyam, B V; Giacobini, E; Ferraro, T N; Hare, T A

1990-11-01

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: Chronic lithium treats most, but not all features

PubMed Central

van Enkhuizen, Jordy; Milienne-Petiot, Morgane; Geyer, Mark A.; Young, Jared W.

2015-01-01

Rationale Bipolar disorder (BD) is a disabling and life-threatening disease characterized by states of depression and mania. New and efficacious treatments have not been forthcoming partly due to a lack of well-validated models representing both facets of BD. Objectives We hypothesized that cholinergic- and dopaminergic-pharmacological manipulations would model depression and mania respectively, each attenuated by lithium treatment. Methods C57BL/6J mice received the acetylcholinesterase inhibitor physostigmine or saline before testing for ‘behavioral despair’ (immobility) in the tail-suspension test (TST) and forced-swim test (FST). Physostigmine effects on exploration and sensorimotor gating were assessed using the cross-species behavioral pattern monitor (BPM) and prepulse inhibition (PPI) paradigms. Other C57BL/6J mice received chronic lithium drinking water (300, 600, or 1200 mg/l) before assessing their effects alone in the BPM or with physostigmine on FST performance. Another group was tested with acute GBR12909 (dopamine transporter inhibitor) and chronic lithium (1000 mg/l) in the BPM. Results Physostigmine (0.03 mg/kg) increased immobility in the TST and FST without affecting activity, exploration, or PPI. Lithium (600 mg/l) resulted in low therapeutic serum concentrations and normalized the physostigmine-increased immobility in the FST. GBR12909 induced mania-like behavior in the BPM of which hyper-exploration was attenuated, though not reversed, after chronic lithium (1000 mg/ml). Conclusions Increased cholinergic levels induced depression-like behavior and hyperdopaminergia induced mania-like behavior in mice, while chronic lithium treated some, but not all, facets of these effects. These data support a cholinergic-monoaminergic mechanism for modeling BD aspects and provide a way to assess novel therapeutics. PMID:26141192

Blood Cholinesterase as a Function of Physostigmine.

DTIC Science & Technology

1981-07-01

organophosphates to serum cholines - terase and brain homogenate are similar, indicating that the en- zymes are the same in blood and brain, although...organophosphate insult to the organism. Little research is available on the time course of cholin - esterase inactivation and/or reactivation after...administration. Nine animals received a .05, .07, .09, .11, or .13 mg/kg dose of physostigmine salicylate or a placebo injection on two occasions, and four

Deanol and physostigmine in the treatment of L-dopa-induced dyskinesias.

PubMed

Lindeboom, S F; Lakke, J P

1978-08-01

Deanol and placebo were administered to 10 parkinsonian patients with levodopa-induced dyskinesias in a double-blind, crossover fashion. Deanol and placebo did not differ significantly in their effects on dyskinesias. The reported properties of deanol seem to be attributable to a placebo effect. There was no correlation with the results of the physostigmine test. Despite these disappointing results deanol remains intriguing, because in individual cases remarkable improvements on dyskinesias are reported.

Use of Physostigmine by the Intravenous, Intramuscular, and Oral Routes in the Therapy of Anticholinergic Drug Intoxication

DTIC Science & Technology

1976-05-01

THE THERAPY OF ANTICHOLINERGIC DRUG INTOXJCATION I. INTRODUCTION. The use of physostigmine (as the elixir of the Calabar bean) as an antidote to the...treatment is indicated: (1) The tachycardia may produce a strain on the cardiovascular system, particularly if the patient is elderly or has preexisting... cardiovascular disease; (2) the reduction in ability to lose heat because of sweat inhibition may make the patient susceptible to heat exhaustion or

Graduate Education and Simulation Training for CBRNE Disasters Using a Multimodal Approach to Learning. Part 2: Education and Training from the Perspectives of Educators and Students

DTIC Science & Technology

2013-08-01

anesthetized NHPs exposed to the carbamate nerve-agent simulant physostigmine, which is FDA-approved for the diagnosis and treatment of myasthenia ... gravis . Physostigmine is a short-acting drug that reliably induces the cholinergic signs of increased secretions (lacrimation, hypersalivation...the experience. One insightful comment is provided below. “As an MD, I have treated myasthenia crisis and delirium tremens. I can say definitely

Co2(CO)8-catalyzed intramolecular hetero-Pauson-Khand reaction of alkynecarbodiimide: synthesis of (+/-)-physostigmine.

PubMed

Mukai, Chisato; Yoshida, Tatsunori; Sorimachi, Mao; Odani, Akira

2006-01-05

[reaction: see text] Herein we describe a novel Co(2)(CO)(8)-catalyzed intramolecular aza-Pauson-Khand-type reaction of alkynecarbodiimide derivatives affords pyrrolo[2,3-b]indol-2-one ring systems in reasonable yields. This is the first reported Co(2)(CO)(8) successfully applied in the hetero-Pauson-Khand reaction. Significantly, the transformation of one of our pyrrolo[2,3-b]indol-2-one derivatives into the indole alkaloid, (+/-)-physostigmine, was completed in a highly stereoselective manner.

Intrinsic Cholinergic Mechanisms Regulating Cerebral Blood Flow as a Target for Organophosphate Action.

DTIC Science & Technology

1985-10-01

regions one hour 26 following microinjection of YH- choline into the right parietal cortex. II Effect of atropine sulfate (0.3 mg/kg i.v.) on the...Harvard Apparatus model 940). The superfusate consisted of a modified Kreb’s- bicarbonate buffer containing physostigmine to inhibit ACh degradation...in mM: NaCl, 118; CaCI 2 , 1.2; KC01, 4.8; MgSO4, 1.2; NaH 2 PO 4 , 1.2; NaHCO 3 , 25; choline chloride, 0.001; physostigmine, 0.1). The area of the

Hippocampal theta, gamma, and theta-gamma coupling: effects of aging, environmental change, and cholinergic activation

PubMed Central

Jacobson, Tara K.; Howe, Matthew D.; Schmidt, Brandy; Hinman, James R.; Escabí, Monty A.

2013-01-01

Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics of encoding and retrieval. One major influence on hippocampal rhythmicity is from cholinergic afferents. In both humans and rodents, aging is linked to impairments in hippocampus-dependent function along with degradation of cholinergic function. Cholinomimetics can reverse some age-related memory impairments and modulate oscillations in the hippocampus. Therefore, one would expect corresponding changes in these oscillations and possible rescue with the cholinomimetic physostigmine. Hippocampal activity was recorded while animals explored a familiar or a novel maze configuration. Reexposure to a familiar situation resulted in minimal aging effects or changes in theta or gamma oscillations. In contrast, exploration of a novel maze configuration increased theta power; this was greater in adult than old animals, although the deficit was reversed with physostigmine. In contrast to the theta results, the effects of novelty, age, and/or physostigmine on gamma were relatively weak. Unrelated to the behavioral situation were an age-related decrease in the degree of theta-gamma coupling and the fact that physostigmine lowered the frequency of theta in both adult and old animals. The results indicate that age-related changes in gamma and theta modulation of gamma, while reflecting aging changes in hippocampal circuitry, seem less related to aging changes in information processing. In contrast, the data support a role for theta and the cholinergic system in encoding and that hippocampal aging is related to impaired encoding of new information. PMID:23303862

Pharmacological management of anticholinergic delirium - theory, evidence and practice.

PubMed

Dawson, Andrew H; Buckley, Nicholas A

2016-03-01

The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded. This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re-dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non-pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01-0.02 mg kg(-1) in children) with a minimum delay of 10-15 min before re-dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting. © 2015 The British Pharmacological Society.

Acetylcholinesterase inhibition and anti-Soman efficacy of homologs of physostigmine. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, L.W.; Anderson, D.R.; Pastelak, A.M.

1992-12-31

Inhibition of acetylcholinesterase (AChE) activity by physostigmine (PHY) is reversible due to spontaneous decarbamylation. Physostigmine has been shown to be effective as a pretreatment against potent anticholinesterase poisons (e.g., soman) in experimental animals, yet it is short acting and causes undesirable side effects in mammals. The two-fold purpose of this study was (1) to determine whether extension of the N-substituted alkyl chain (N-SAC) of PHY from N-methyl to N-ethyl (1), N-propyl (2), N-isopropyl (3), N-butyl (4) or N-heptyl (5) affects anti-AChE potency and spontaneous decarbamylation of inhibited AChE of guinea pig blood in vitro and in vivo and (2) tomore » see whether chain extension affects efficacy as pretreatment in poisoning by soman. The in vitro AChE inhibition studies were done using whole blood incubated at 37 deg C for 30 min. All 5 homologs possessed anti-AChE activity with I50s ranging from 1.1 to 27.6 x l0(-7)M; compound III was the least potent in vitro and in vivo. Lengthening of the N-SAC of PHY markedly extended the duration of anti-AChE activity when compared to PHY, but rendered the modified compounds ineffective as pretreatments against soman. These data support the premise that the decrease in decarbamylation rates observed upon extending the N-SAC of PHY is responsible for the loss of effectiveness of pretreatment regimens against soman. Perhaps, these homologs of PHY may have potential use in instances where sustained action of acetylcholine is required at cholinergic junctions because of disease conditions or drug overdosage.... Physostigmine, Nerve agent pretreatment, Soman, Acetylcholinesterase inhibition.« less

Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge

PubMed Central

Li, Xiufeng; Spence, Jeffrey S.; Buhner, David M.; Hart, John; Cullum, C. Munro; Biggs, Melanie M.; Hester, Andrea L.; Odegard, Timothy N.; Carmack, Patrick S.; Haley, Robert W.

2011-01-01

Purpose: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. Materials and Methods: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups—syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)—and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. Results: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. Conclusion: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition. © RSNA, 2011 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101715/-/DC1 PMID:21914840

[Etiology of initially unexplained confusion of excitability in deadly nightshade poisoning with suicidal intent. Symptoms, differential diagnosis, toxicology and physostigmine therapy of anticholinergic syndrome].

PubMed

Heindl, S; Binder, C; Desel, H; Matthies, U; Lojewski, I; Bandelow, B; Kahl, G F; Chemnitius, J M

2000-11-10

After a walk in a wood a 55-year-old teacher was admitted to the emergency unit of a university hospital because of somnolence and excitability. Her rectal temperature was 37.8 degrees C, she had sinus tachycardia (rate of 130/min) but no other significant findings. With the exception of C-reactive protein (10 mg/dl), MCV (101 fl), MCH (34 pg) and arterial blood gases (pH 7.483, pCO2 35.5 mmHg, base excess 5.1 mmp/l) laboratory tests were within normal limits. Qualitative screening of serum for benzodiazepines, barbiturates and antidepressives was negative. Neurological examination, including lumbar puncture and cranial computed tomography were noncontributory. 10 hours after admission the patient developed signs of an anticholinergic syndrome with mydriasis, dry mouth, tachycardia, hot skin and an atonic bladder. Physostigmine 2 mg completely reversed the neurological and mental symptoms. After gas chromatography, mass-spectrometry of a urine sample showed an atropine molecular fragment with a molecular weight of 271. At intervals of 3 to 5 hours the recurrence of confusion and excitability required 4 further i.v. injection of physostigmine. The patient subsequently became accessible to psychiatric examination and reported that during the walk she had swallowed 8-10 berries of deadly nightshade with suicidal intent. In case of excitability and confusion as well as somnolence or coma of uncertain aetiology an anticholinergic syndrome caused by ingestion of atropine-containing plants or psychoactive drugs (phenothiazines, butyrophenones, tri- or tetracyclic antidepressants) should be included in the differential diagnosis. If there are suggestive clinical findings (tachycardia, somnolence, coma or threatened respiratory arrest, physostigmine should be given if there are no contraindications.

Tramadol state-dependent memory: involvement of dorsal hippocampal muscarinic acetylcholine receptors.

PubMed

Jafari-Sabet, Majid; Jafari-Sabet, Ali-Reza; Dizaji-Ghadim, Ali

2016-08-01

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.

The early toxicology of physostigmine: a tale of beans, great men and egos.

PubMed

Proudfoot, Alex

2006-01-01

Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who had reservations, Harley was the most prominent. He concluded that paralysis was secondary to effects on the motor nerve endings and, in so doing, came nearest to present-day knowledge at a time when acetylcholine, cholinesterases and cholinesterase inhibitors were not even imagined. Differences of opinion on the mode of action of the beans were to be expected and it is hardly surprising that they were not resolved. No standard formulation of physostigmine was available so the potency of those used would have varied from one investigator to another, the range of animals experimented upon was large while the number used by any researcher was commonly in single figures, more readily available cold-blooded creatures seemed less sensitive to physostigmine toxicity than warm-blooded ones and only Fraser determinedly pursued an answer; in general, the others made one foray into bean research then turned their attentions elsewhere. The same problems would beset other aspects of bean research. While Fraser did not get as close to the mode of action of physostigmine as Harley, he reigns supreme when it comes to antagonism between physostigmine and atropine. By this time, the 1870s had dawned and although the concept of antagonism between therapeutic agents was not new, it had little, if any, reliable scientific foundation. This was about to change; antagonism was becoming exciting and rational. Fraser's firm belief that physostigmine and atropine were mutually antagonistic at a physiological level was contrary to the conventional wisdom of his contemporaries. This alone would earn him a place in history but his contribution goes much, much further. Unlike any other at the time, he investigated it with scientific rigour, experimenting on only one species, ensuring as best he could the animals were the same weight, adjusting the doses of drugs he gave them for bodyweight, determining the minimum lethal dose of each drug before assessing their antagonistic effects, adopting a single, incontrovertible endpoint for efficacy and carrying out sufficient numbers of experiments to appear convincing in a later era where the statistical power of studies is all-important. To crown it all, he presented his results graphically. Fraser never claimed to have discovered the antagonism between physostigmine and atropine. Bartholow in 1873 did, based on work done in 1869. But his data hardly justify it. If anyone can reasonably claim this particular scientific crown it is an ophthalmologist, Niemetschek, working in Prague in 1864. His colleague in the same discipline, Kleinwächter, was faced with treating a young man with atropine intoxication. Knowing of the contrary actions of the two drugs on the pupil, Niemetschek suggested that Calabar bean extract might be useful. Kleinwächter had the courage to take the advice and his patient improved dramatically. Clearly, this evidence is nothing more than anecdotal, but the ophthalmologists were correct and, to the present day, physostigmine has had an intermittent role in the management of anticholinergic poisoning. The converse, giving atropine to treat poisoning with cholinesterase inhibitors, of which physostigmine was the first, has endured more consistently and remains standard practice today. It is salutary to realise that the doses and dosage frequency of atropine together with the endpoints that define they are adequate were formulated by Fraser and others a century and a half ago.

Effects of oxotremorine and physostigmine on the inhibitory avoidance impairment produced by amitriptyline in male and female mice.

PubMed

Monleón, Santiago; Urquiza, Adoración; Vinader-Caerols, Concepción; Parra, Andrés

2009-12-28

We have previously observed that amitriptyline and other antidepressants produce impairing effects on inhibitory avoidance (also called passive avoidance) in mice of both sexes. In the present study we investigated the involvement of the cholinergic system in the inhibitory avoidance impairment produced by acute amitriptyline in male and female CD1 mice. For this purpose, the effects on said task of acute i.p. administration of several doses of amitriptyline, either alone or in combination with the cholinergic agonists oxotremorine and physostigmine, were evaluated. Pre-training administration of 5, 7.5, 10 or 15 mg/kg of amitriptyline produced a significant impairment of inhibitory avoidance in both males and females. When oxotremorine (0.05 or 0.1 mg/kg) was co-administered with amitriptyline, the antidepressant's impairing effect was partially counteracted, although inhibitory avoidance learning was not significant. Physostigmine (0.15, 0.3 or 0.6 mg/kg) counteracted the impairment produced by amitriptyline, as mice treated with both drugs exhibited inhibitory avoidance learning. These results show that the inhibitory avoidance impairment produced by amitriptyline in male and female mice is mediated, at least partially, by the cholinergic system.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harris, L.W.; Talbot, B.G.; Lennox, W.J.

A pretreatment for organophosphorus (OP) anticholinesterase (e. g. , soman) intoxication should prevent lethality and convulsions (CNV) at 2 LD50s and be behavioral-decrement-free when given alone. Behavioral-deficit-free pretreatment regimens (PRGs) for guinea pigs consisted of Physostigmine (0.15 mg/kg, im) and adjunct. Adjuncts MG/KG, IM tested were akineton 0.25, aprophen 8, trihexyphenidyl 2, atropine 16, azaprophen 51, BENACTYZINE 1.25, cogentin 4, dextromethorphan 7.5, ethopropazine 12, kemadrin 11, MEMANTINE 5, promethazine 5, scopolamine 0.081 AND CONTROL 2. PRGs were given 30 min before soman (60 ug/kg, sc; 2 LD50S) or other OP agents. Animals were then observed and graded for signs ofmore » intoxication, including CNV at 7 time points and at 24 hr. Physostigmine alone reduced the incidence of CNV and lethality induced by 2 LD50s of soman by 42 and 60%, respectively. All of the PRGs tested abolished lethality and 12 shortened recovery time to 2 hr or less. Also, PRGs including azaprophen or atropine prevented CNV. When selected PRGs were tested against intoxication by sarin, tabun or VX, the efficacy was generally superior to that for soman. The data show that several PRGs are effective against soman intoxication in guinea pigs. Pretreatment, physostigmine, anticholinesterases, soman (GD).« less

The combined effects of pyridostigmine and chronic stress on brain cortical and blood acetylcholinesterase, corticosterone, prolactin and alternation performance in rats.

PubMed

Kant, G J; Bauman, R A; Feaster, S R; Anderson, S M; Saviolakis, G A; Garcia, G E

2001-01-01

Thousands of soldiers who served in the Gulf War have symptoms that have been collectively termed Gulf War Illness (GWI). It has been suggested that a combination of operational stress and pyridostigmine, a drug given as a pretreatment to protect soldiers against the effects of exposure to nerve agents, might have had unexpected adverse health effects causing these symptoms. Our laboratory has previously modeled operational stress in rats using a paradigm of around-the-clock intermittent signalled footshock. In the present studies, this model was used to investigate the potential synergistic effects of chronic stress and pyridostigmine on physiology and behavior. Seventy-two rats were trained to perform an alternation lever pressing task to earn their entire daily food intake. The rats were then implanted with osmotic minipumps containing vehicle, pyridostigmine (25 mg/ml pyridostigmine bromide) or physostigmine (20 mg/ml eserine hemisulfate). The pumps delivered 1 microl/h, which resulted in a cumulative dosing of approximately 1.5 mg/kg/day of pyridostigmine or 1.2 mg/kg/day of physostigmine, equimolar doses of the two drugs. The rats were then returned to their home cages where performance continued to be measured 24 h/day. After 4 days, 24 of the 72 rats were trained to escape signalled footshock (avoidance-escape group) and 24 other rats (yoked-stressed group) were each paired to a rat in the avoidance-escape group. The remaining 24 rats were not subjected to footshock (unstressed group). Shock trials were intermittently presented in the home cage 24 h/day for 3 days, while alternation performance continued to be measured. Since only 12 test cages were available, each condition was repeated to achieve a final n of six rats per group. Pyridostigmine and physostigmine each decreased blood acetylcholinesterase levels by approximately 50%. Physostigmine also decreased brain cortical acetylcholinesterase levels by approximately 50%, while pyridostigmine had no effect on cortical acetylcholinesterase activity. Alternation performance was impaired on the first day of stress and then recovered. Neither pyridostigmine nor physostigmine affected performance in the absence of stress or increased the effects of stress alone. Corticosterone was significantly increased in the yoked stress group compared to unstressed controls. These data suggest that pyridostigmine does not exacerbate the effects of stress on performance or levels of stress hormones. Furthermore, these data do not suggest that stress enables pyridostigmine to cross the blood brain barrier.

Reversal of androgen inhibition of estrogen-activated sexual behavior by cholinergic agents.

PubMed

Dohanich, G P; Cada, D A

1989-12-01

Androgens have been found to inhibit lordosis activated by estrogen treatment of ovariectomized female rats. In the present experiments, dihydrotestosterone propionate (200 micrograms for 3 days) inhibited the incidence of lordosis in ovariectomized females treated with estradiol benzoate (1 microgram for 3 days). This inhibition of lordosis was reversed 15 min after bilateral intraventricular infusion of physostigmine (10 micrograms/cannula), an acetylcholinesterase inhibitor, or carbachol (0.5 microgram/cannula), a cholinergic receptor agonist. This reversal of inhibition appears to be mediated by cholinergic muscarinic receptors since pretreatment with scopolamine (4 mg/kg, ip), a muscarinic receptor blocker, prevented the reversal of androgen inhibition by physostigmine. These results indicate that androgens may inhibit estrogen-activated lordosis through interference with central cholinergic muscarinic mechanisms.

The output per stimulus of acetylcholine from cerebral cortical slices in the presence or absence of cholinesterase inhibition

PubMed Central

Bourdois, P.S.; Mitchell, J.F.; Somogyi, G.T.; Szerb, J.C.

1974-01-01

1 The release of endogenous acetylcholine (ACh) from cerebral cortical slices stimulated at 0.25, 1, 4, 16 and 64 Hz was measured in the presence either of physostigmine or of physostigmine and atropine. 2 Atropine potentiated the evoked release of endogenous ACh especially at low frequencies resulting in an output per stimulus which sharply declined with increasing frequency of stimulation, while in the absence of atropine the output of ACh per stimulus was low and fairly constant. 3 The evoked release of [3H]-ACh per stimulus following the incubation of the slices with [3H]-choline, as estimated by means of rate constants of the evoked release of total radioactivity, showed a frequency dependence similar to endogenous ACh when the two were tested under identical conditions. 4 In the absence of an anticholinesterase the evoked release of [3H]-ACh per stimulus was dependent on frequency of stimulation in a similar way to that in the presence of physostigmine and atropine. 5 Results suggest that under physiological conditions, i.e. in the absence of an anti-cholinesterase, the release of ACh per stimulus decreases with increasing frequency of stimulation and that this decrease is due to a lag in the mobilization of stored ACh rather than in the synthesis of new ACh. PMID:4455327

Interactions between scopolamine and muscarinic cholinergic agonists or cholinesterase inhibitors on spatial alternation performance in rats.

PubMed

Shannon, H E; Bemis, K G; Hendrix, J C; Ward, J S

1990-12-01

The effects on working memory of the muscarinic cholinergic agonists oxotremorine, arecoline, RS86 and pilocarpine, and the cholinesterase inhibitors physostigmine and tetrahydroaminoacadine were investigated in male F344 rats. Working memory was assessed by behavior maintained under a spatial alternation schedule of food presentation in which the interval between trials was varied from 2 to 32 sec. Under control conditions the percentage of correct responses decreased as the retention interval was varied from 2 to 32 sec. Administered alone the cholinergic agonists oxotremorine (0.01-0.1 mg/kg), arecoline (3-30 mg/kg), RS86 (0.3-3 mg/kg) and pilocarpine (0.3-3.0 mg/kg), and the cholinesterase inhibitors physostigmine (0.01-0.1 mg/kg) and tetrahydroaminoacridine (0.3-3.0 mg/kg) either had no effect on or produced dose-related deficits in working memory and decreases in response rates. The muscarinic antagonist scopolamine (0.1 mg/kg) produced retention interval-dependent decreases in the percentage of correct responding and rates of responding. The cholinergic agonists and tetrahydroaminoacridine failed to reverse the effects of scopolamine. However, physostigmine produced a dose-dependent reversal of the working-memory deficits and response-rate decreasing effects of scopolamine. The present results are consistent with the interpretation that drugs which primarily enhance M2 muscarinic cholinergic transmission are ineffective in enhancing working memory or in reversing scopolamine-induced deficits in working memory.

In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat.

PubMed

Killi, Uday K; Wsol, Vladimir; Soukup, Ondrej; Kuca, Kamil; Winder, Michael; Tobin, Gunnar

2014-02-01

Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime. © 2013 Wiley Publishing Asia Pty Ltd.

Effect of oxotremorine, physostigmine, and scopolamine on brain acetylcholine synthesis: a study using HPLC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertrand, N.; Beley, A.

The synthesis rate of brain acetylcholine (ACh) was estimated in mice following i.v. administration of ({sup 3}H)choline (Ch). The measurements were performed 1 min after the tracer injection, using the ({sup 3}H)ACh/({sup 3}H)Ch specific radioactivity ratio as an index of ACh synthesis rate. Endogenous and labeled Ch and ACh were quantified using HPLC methodology. Oxotremorine and physostigmine (0.5 mg/kg, i.p.) increased the steady state concentration of brain ACh by + 130% and 84%, respectively and of Ch by + 60% (oxotremorine); they decreased ACh synthesis by 62 and 55%, respectively. By contrast, scopolamine (0.7 mg/kg, i.p.) decreased the cerebral contentmore » of Ch by - 26% and of ACh by - 23% without enhancing the synthesis of ACh. The results show the utility of HPLC methodology in the investigation of ACh turnover.« less

Interaction between physostigmine and soman on brain regional cholinesterase activity and /sup 3/H-physostigmine distribution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hallak, M.E.; Woodruff, E.; Giacobini, E.

1986-03-05

Physostigmine (Phy) concentrations (as radioactivity) were studied in various brain areas after /sup 3/H-Phy administration as a function of time. Five min after 500 ..mu..g/kg i.m., cortex (CX) and total brain showed similar concentrations (370 ng/g) which were 50-90% higher than those of other brain regions (striatum, hippocampus, and medulla oblongata). Soman did not affect Phy levels in whole brain after pretreatment with Phy (100 or 500 ..mu..g/kg), however, the regional distribution of Phy was altered by soman as was ChE inhibition. A significant increase in Phy concentration was seen in HC (22 and 45% at 5 and 30 min,more » respectively) and CX (21% at 30 min). ChE activity in total brain was 12, 30, and 24% (5, 15 and 30 min after soman administration) lower than after Phy alone. If the pretreatment dose of Phy was increased to 500 ..mu..g/kg /sup 3/H-Phy, ChE activity was further reduced to 4, 13 and 19%. This might indicate that higher doses of Phy provide more protection of the enzyme from soman than lower doses. The protective role of Phy seen in total brain was not consistent for all brain regions. Soman alone produced a 95% ChE inhibition and there were no differences in its effect between total brain or brain areas. Pretreatment of the rat with Phy produced a protective effect upon ChE activity up to 30 min. However, no protective effect on survival was observed.« less

Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (−)-[18F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain☆

PubMed Central

Hillmer, A.T.; Esterlis, I.; Gallezot, J.D.; Bois, F.; Zheng, M.Q.; Nabulsi, N.; Lin, S.F.; Papke, R.L.; Huang, Y.; Sabri, O.; Carson, R.E.; Cosgrove, K.P.

2016-01-01

The positron emission tomography (PET) radioligand (−)-[18F]flubatine is specific to α4β2∗ nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4β2∗ nAChR quantification with bolus plus constant infusion (B/I) (−)-[18F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n = 8) or B/I (n = 4) administration of (−)-[18F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n = 6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5 mg over 60 min beginning 5 min prior to radiotracer injection); 2. A single scan B/I paradigm (n = 7) lasting up to 240 min with 1.5 mg physostigmine administered over 60 min beginning at 125 min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8 ± 3.3 mL/cm3 in thalamus, 12.9 ± 1.6 mL/cm3 in cerebellum, and ranged from 9.8 to 12.5 mL/cm3 in other gray matter regions. The B/I paradigm with equilibrium analysis at 120 min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (−)-[18F]flubatine VT/fP in 120 min, and suggest possible sensitivity of (−)-[18F]flubatine binding to physostigmine-induced changes in acetylcholine levels. PMID:27426839

Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (-)-[(18)F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain.

PubMed

Hillmer, A T; Esterlis, I; Gallezot, J D; Bois, F; Zheng, M Q; Nabulsi, N; Lin, S F; Papke, R L; Huang, Y; Sabri, O; Carson, R E; Cosgrove, K P

2016-11-01

The positron emission tomography (PET) radioligand (-)-[(18)F]flubatine is specific to α4β2(⁎) nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4β2(⁎) nAChR quantification with bolus plus constant infusion (B/I) (-)-[(18)F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n=8) or B/I (n=4) administration of (-)-[(18)F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n=6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5mg over 60min beginning 5min prior to radiotracer injection); 2. A single scan B/I paradigm (n=7) lasting up to 240min with 1.5mg physostigmine administered over 60min beginning at 125min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8±3.3mL/cm(3) in thalamus, 12.9±1.6mL/cm(3) in cerebellum, and ranged from 9.8 to 12.5mL/cm(3) in other gray matter regions. The B/I paradigm with equilibrium analysis at 120min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (-)-[(18)F]flubatine VT/fP in 120min, and suggest possible sensitivity of (-)-[(18)F]flubatine binding to physostigmine-induced changes in acetylcholine levels. Copyright © 2016 Elsevier Inc. All rights reserved.

Autoregulation of Neuromuscular Transmission by Nerve Terminals.

DTIC Science & Technology

1985-09-01

prejunctional cholinoceptor. Nicotine, carbachol , ACh and suberyl- dicholine have been used as agonists. 1 , 2 Neostigmine (NEO) and related acetylcholinesterase...bromide, aminopyridine, aBGT, DFP, nicotine, carnitine, dTC, physostigmine and carbachol . A one-way analysis of variance of these data indicated a lack

Cholinoceptive and cholinergic properties of cardiomyocytes involving an amplification mechanism for vagal efferent effects in sparsely innervated ventricular myocardium.

PubMed

Kakinuma, Yoshihiko; Akiyama, Tsuyoshi; Sato, Takayuki

2009-09-01

Our recent studies have shown that, as indicated by vagal stimulation, an acetylcholinesterase inhibitor donepezil, an anti-Alzheimer's disease drug, prevents progression of heart failure in rats with myocardial infarction, and activates a common cell survival signal shared by acetylcholine (ACh) in vitro. On the basis of this and evidence that vagal innervation is extremely poor in the left ventricle, we assessed the hypothesis that ACh is produced by cardiomyocytes, which promotes its synthesis via a positive feedback mechanism. Rat cardiomyocytes expressed choline acetyltransferase (ChAT) in the cytoplasm and vesicular acetylcholine transporter with the vesicular structure identified by immunogold electron microscopy, suggesting that cardiomyocytes possess components for ACh synthesis. Intracellular ACh in rat cardiomyocytes was identified with physostigmine or donepezil. However, with atropine, the basal ACh content was reduced. In response to exogenous ACh or pilocarpine, cardiomyocytes increased the transcriptional activity of the ChAT gene through a muscarinic receptor and ChAT protein expression, and, finally, the intracellular ACh level was upregulated by pilocarpine. Knockdown of ChAT by small interfering RNA accelerated cellular energy metabolism, which is suppressed by ACh. Although physostigmine had a minimal effect on the ChAT promoter activity by inhibiting acetylcholinesterase, donepezil resulted in elevation of the activity, protein expression and intracellular ACh level even in the presence of sufficient physostigmine. Orally administered donepezil in mice increased the ChAT promoter activity in a reporter gene-transferred quadriceps femoris muscle and the amount of cardiac ChAT protein. These findings suggest that cardiomyocytes possess an ACh synthesis system, which is positively modulated by cholinergic stimuli. Such an amplification system in cardiomyocytes may contribute to the beneficial effects of vagal stimulation on the ventricles.

Effects of intra-hippocampal microinjection of vitamin B12 on the orofacial pain and memory impairments induced by scopolamine and orofacial pain in rats.

PubMed

Erfanparast, Amir; Tamaddonfard, Esmaeal; Nemati, Shaghayegh

2017-03-01

In the present study, we investigated the effects of microinjection of vitamin B 12 into the hippocampus on the orofacial pain and memory impairments induced by scopolamine and orofacial pain. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Orofacial pain was induced by subcutaneous injection of formalin (1.5%, 50μl) into the right vibrissa pad, and the durations of face rubbing were recorded at 3-min blocks for 45min. Morris water maze (MWM) was used for evaluation of learning and memory. Finally, locomotor activity was assessed using an open-field test. Vitamin B 12 attenuated both phases of formalin-induced orofacial pain. Prior administration of naloxone and naloxonazine, but not naltrindole and nor-binaltorphimine, prevented this effect. Vitamin B 12 and physostigmine decreased latency time as well as traveled distance in Morris water maze. In addition, these chemicals improved scopolamine-induced memory impairment. The memory impairment induced by orofacial pain was improved by vitamin B 12 and physostigmine used alone. Naloxone prevented, whereas physostigmine enhanced the memory improving effect of vitamin B 12 in the pain-induced memory impairment. All the above-mentioned chemicals did not alter locomotor activity. The results of the present study showed that at the level of the dorsal hippocampus, vitamin B 12 modulated orofacial pain through a mu-opioid receptor mechanism. In addition, vitamin B 12 contributed to hippocampal cholinergic system in processing of memory. Moreover, cholinergic and opioid systems may be involved in improving effect of vitamin B 12 on pain-induced memory impairment. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of larkspur (Delphinium barbeyi) on heart rate and electrically evoked electromyographic response of the external anal sphincter in cattle.

PubMed

Green, Benedict T; Pfister, James A; Cook, Daniel; Welch, Kevin D; Stegelmeier, Bryan L; Lee, Stephen T; Gardner, Dale R; Knoppel, Edward L; Panter, Kip E

2009-04-01

OBJECTIVE-To determine whether larkspur-derived N-(methylsuccinimido) anthranoyllycoctonine (MSAL)-type alkaloids alter heart rate and electrically evoked electromyographic (eEMG) response of the external anal sphincter (EAS) in cattle and whether these effects can be reversed by acetylcholinesterase inhibitors. ANIMALS-12 beef heifers and 4 cows. PROCEDURES-3 or 4 heifers were used in 1 or 2 of 7 dose-response experiments; heart rate and EAS eEMG response were assessed before and 24 hours after oral treatment with larkspur (doses equivalent to 0.5 to 15 mg of MSAL-type alkaloids/kg). In 3 subsequent experiments, 3 heifers (1 of which was replaced with another heifer in the control experiment) each received 10 mg of MSAL-type alkaloids/kg and were injected IV with physostigmine (0.04 mg/kg), neostigmine (0.04 mg/kg), or saline (0.9% NaCl) solution 24 hours later, prior to assessment. Additionally, EAS eEMG response was measured in 4 cows before and after epidural administration of 2% lidocaine hydrochloride. RESULTS-Larkspur-treated heifers developed dose-related increases in heart rate and decreases in EAS eEMG response. Twenty-four hours after administration of MSAL-type alkaloids, neostigmine decreased heart rate but did not affect eEMG response, whereas physostigmine did not affect heart rate but caused a 2-fold increase in eEMG response. In cows, epidural anesthesia did not alter eEMG response, suggesting that transdermal stimulation of the EAS pudendal innervation did not occur. CONCLUSIONS AND CLINICAL RELEVANCE-In cattle, cardiac effects and muscle weakness or loss of EAS eEMG response induced by larkspur-derived MSAL-type alkaloids were reversed by neostigmine or physostigmine, respectively. Treatment with anticholinesterase inhibitors may alter the clinical effects of larkspur poisoning in cattle.

Regional Blood-Brain Barrier Responses to Central Cholinergic Activity

DTIC Science & Technology

1989-07-30

i.e., oxotremorine, pilocarpine, carbachol , physostigmine [Olney et al., 1983]). These are some of the same regions affected by soman-induced...Diehl et al., 1984). Carbachol kindling also has been reported (Wasterlain, 1989), linking the cholinergic system to an increase in the sensitivity to

Protection against soman and sarin exposure by transdermal physostigmine and scopolamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meshulam, Y.; Davidovici, R.; Levy, A.

1993-05-13

The purpose of this study was to evaluate the prophylactic efficacy of physostigmine (physo), administered via sustained release (SR) methods, with and without scopolamine, against soman and sarin exposure in guinea-pigs. Transdermal physo pad (3 sq cm/kg; 60-80 ug/sq cm), containing a vehicle based on propionic acid, was applied onto the dorsal back of the animals, 24 hours before exposure to the cholinesterase (ChE) inhibitors. At the time of exposure, physo concentrations in brain and plasma were 3.6 ng/g and 4.1 ng/ml respectively. Brain and whole blood ChE activity were inhibited to 70% and 57% of their original activity. Transdermalmore » physo by itself protected up to 70% of the animals exposed to 1.5 LD(50) of soman or sarin (100% mortality was recorded in the control group). Combining transdermal physo with Scopoderm (by Ciba Geigy Inc.) provided full protection against 1.5 LD(50).« less

Cholinergic Neurotoxicity: Mechanisms and Prevention

DTIC Science & Technology

1986-10-30

carbachol or acetylcholine (ACh) esterase inhibitors , physostigmine or neostigmine( 5,6). Systemic injection of pilo, either alone or preceded by...access to food and water, were used in all experiments. Li and pilo (Sigma Chemical, St. ~ . o. m m mm,,m 1 unmammalaa nnn a I nln l 1 ~nlnnm 1 1

Lessons to be learned: a case study approach. Unseasonal severe poisoning of two adults by deadly nightside (Atropa belladonna).

PubMed

Southgate, H J; Egerton, M; Dauncey, E A

2000-06-01

Unseasonal, mid-winter, severe poisoning by deadly nightshade is reported in two adults who simultaneously ate from a pie made of frozen deadly nightshade berries, mistaken at the time of picking for bilberries. Atropine levels are reported in the urine. Physostigmine treatment was ineffective.

Percy Julian, Robert Robinson, and the Identity of Eserethole

ERIC Educational Resources Information Center

Ault, Addison

2008-01-01

The Nova production "Percy Julian--Forgotten Genius" included the very public disagreement between Percy Julian, an unknown American chemist, and Robert Robinson, possibly the best known organic chemist of the day, as to the identity of "eserethole", the key intermediate for the synthesis of the alkaloid physostigmine. The Nova production,…

Huperzine a as a pretreatment candidate drug against nerve agent toxicity. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grunwald, J.; Raveh, L.; Doctor, B.P.

1994-12-31

Huperzine A (HUP) is a naturally-occurring, potent, reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. To examine its ability to protect against nerve agent poisoning, HUP was administered i.p. to mice, and the s.c. LD50 of soman was determined at various time intervals after pretreatment. Results were compared to those obtained for animals treated with physostigmine. A protective ratio of approximately 2 was maintained for at least 6 hr after a single injection of HUP, without the need for any post-challenge drug therapy. By contrast, pretreatment with physostigmine increased the LD50 of soman by 1.4- to 1.5-fold formore » only up to 90 min. The long-lasting antidotal efficacy displayed by HUP correlated with the time course of the blood-AChE inhibition. The results suggest that the protection of animals by HUP from soman poisoning was achieved by temporarily sequestering the active site region of the physiologically important AChE.« less

Lung function requirements in flying duty the problem of bronchial hyperresponsiveness in military aircrew.

PubMed

Hartmann, C M; Steinhoff-Lankes, D; Maya-Pelzer, P

1999-09-09

Uncompromised lung function is essential for fitness to fly. Under hypobaric conditions there is an increased risk of hypoxemia. G-forces, positive pressure breathing and anti-G maneuvers cause physical stress to the lung tissue and altered pulmonary blood flow. Breathing with pure oxygen, dry cabin air and ozone can cause airway irritation. Chemically and physically by irritating agents may be present. Emergencies such as smoke in the cockpit or inhalation of tear gas can rapidly compromise the pulmonary system in susceptible persons. Sudden incapacitation may occur. Trapped gases may cause overinflation and lung rupture in rapid decompression. Applicants for military duty have to pass basic lung function tests routinely. Preselection of aircrew candidates tends to be even stricter. Asthma and obstructive lung disease are disqualifying. Trained aircrew with late onset of pulmonary problems can be waived under certain restrictions in many cases. Some national regulations exclude even applicants with allergies. Due to aeromedical experience we should always be aware of the latent unspecific bronchial hyperresponsiveness (BHR). BHR is one of the characteristics of asthma bronchiale. If BHR exists there is an increased risk of later development of asthma bronchiale, especially together with perennial allergies such as against house dust mite. Under certain conditions BHR can become symptomatic and aeromedically relevant. In some cases we saw an exacerbation under medication, mostly under beta-receptor-blockers. In one case even under betablocker-containing eye drops. In the Gulf War 1991 a number of allied military personnel had to be withdrawn because of bronchospastic symptoms. This can be explained among others by medication with physostigmine. Physostigmine is a systemically active cholinergic drug which is prophylactically used under threat of chemically warfare agents. In individuals with latent BHR physostigmine will lower the threshold for bronchial reactions considerably and even cause manifest bronchospasm. We recommend an unspecific bronchial challenge test in the selection of personnel for duties where uncompromised lung function under all environmental conditions is essential.

Cholinergic effects on fear conditioning I: the degraded contingency effect is disrupted by atropine but reinstated by physostigmine.

PubMed

Carnicella, Sebastien; Pain, Laure; Oberling, Philippe

2005-04-01

The cholinergic system has been shown to modulate contextual fear conditioning. However, with the exception of trace conditioning studies, most of the available data have focussed on independent context, i.e., context that do not compete with the conditioned stimulus to control for the conditioned response (interactive context). In the present series of experiments, the effects of the muscarinic antagonist, atropine, were assessed when contextual fear memory interacts with cued fear memory to regulate conditioned response, using a Pavlovian degraded contingency preparation in rats. This preparation not only afforded an insight into simple Pavlovian associations but also enabled us to test for the processes of competition that made use of these associations to make an appropriate response to a stimulus [degraded contingency effect (DCE)]. In experiment 1, three doses of atropine [2.5, 5.0, and 10.0 mg/kg, intraperitoneally (i.p.)] were evaluated on male Sprague-Dawley rats. In experiment 2, physostigmine (0.037-0.3 mg/kg, i.p.) was injected after the administration of 5 mg/kg of atropine. Experiment 1A and its partial replication (experiment 1B) showed that at asymptotic level of training, atropine did not alter contextual and cued fear memories when the subjects were directly tested for them, whereas it suppressed the DCE for a 5 mg/kg dose. Indeed, atropine-induced suppression of the DCE was found to be an inverted U-shaped dose-response curve. Experiment 2 showed that physostigmine caused a dose-dependent reversal of the atropine-induced alleviation of the DCE, without altering the expression of simple cued and contextual fear memories. These results evidence at asymptotic level of training a cholinergic modulation of the processing of interactive context, but not of independent ones. They are discussed in the framework of the mechanisms that are involved in both types of contextual processing.

A Pharmacokinetic Study of the Effects of Stress and Exercise on Chemical Exposure

DTIC Science & Technology

2001-03-20

Organophosphates such as diazinon and malathion are considered cholinesterase inhibitors, while carbamates such as physostigmine and pyridostigmine...bromide (PB) are considered reversible cholinesterase inhibitors. The possible Gulf War exposures to organophosphates such as diazinon and malathion...indicate that the physiological and protective effects of carbamates such as PB may depend on a narrow range of cholinesterase inhibition. Blood

High Peak Power Microwaves: A Health Hazard

DTIC Science & Technology

1993-12-01

activity and/or neural transmission"I4 1. For example, we I have reported electromagnetically induced effects, such as corneal endothelial lesions...increased permeability of the iris vasculature, altered retinal electrophysiologic activity (visual function), and histopathological changesr. The...level"]. The electromagnetic environment can also alter the drug’s action, as has been demonstrated with the anticholinesterase drug, physostigmineM

DEPRESSION OF THE PHOTIC AFTER DISCHARGE OF FLASH EVOKED POTENTIALS BY PHYSOSTIGMINE, CARBARYL AND PROPOXUR AND THE RELATIONSHIP TO INHIBITION OF BRAIN CHOLINESTERASE

EPA Science Inventory

The effects of N-methyl carbamate pesticides on the photic after discharge (PhAD) of flash evoked potentials (FEPs) and the relationship between inhibition of brain cholinesterase (ChE) activity and the PhAD were evaluated. FEPs were recorded in Long Evans rats treated with physo...

In vivo dose response relationship between physostigmine and cholinesterase activity in RBC and tissues of rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Somani, S.M.; Dube, S.N.

1989-01-01

Dose response of physostigmine (Phy) was studied in rat using various doses. Rats were sacrificed 15 min after Phy administration. Blood and tissues were analyzed for ChE activity by radiometric method and Phy concentration by HPLC method. A comparison of ChE values in different tissues of rats indicated that ChE activity was highest in brain and least in diaphragm. The enzyme activity was eleven times more in brain as compared to diaphragm. Phy produced a dose-dependent inhibition of ChE in RBC, brain and diaphragm from 50 to 200 {mu}g/kg, then ChE inhibition was plateaued from 200 to 500 {mu}g/kg inmore » these tissues. A dose related ChE inhibition was seen in heart and thigh muscle from 50 to 500 {mu}g/kg. Phy concentration increased linearly from 50 to 400 {mu}g/kg in plasma, brain, heart and thigh muscle. These results indicate that ChE inhibition is linear up to 200 {mu}g/kg in RBC, 150 {mu}g/kg in brain and 300 {mu}g/kg in heart. This linearity is not consistent in other tissues.« less

Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis.

PubMed

Murray, C L; Fibiger, H C

1986-02-01

The effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (nBM) on the acquisition and retention of several spatial memory tasks were studied in the rat. Maintenance of spatial memory in a food search task was impaired following nBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze was also significantly impaired in animals with these lesions. In contrast, the animals with nBM lesions were not impaired in the acquisition of a position habit in a T-maze. In several of the tasks there was evidence of some learning in the lesion animals after substantial training, although they were significantly deficient when compared with the controls. Administration of the cholinergic agonists physostigmine sulfate or pilocarpine nitrate prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesion animals. The ibotenate-induced lesions significantly reduced the activity of choline acetyltransferase (CAT) in the anterior and the posterior neocortex. Hippocampal CAT activity was not changed. The results indicate that the cholinergic projections originating in the nBM are involved in the learning and memory of spatial tasks.

Effect of endogenous tachykinins on neuro-effector transmission of vagal nerve in guinea-pig tracheal tissue.

PubMed

Aizawa, H; Miyazaki, N; Inoue, H; Ikeda, T; Shigematsu, N

1990-01-01

To elucidate the effect of endogenous tachykinins on neuro-effector transmission of vagal nerves, we performed in vitro experiments using guinea-pig tracheal smooth muscle. The subthreshold dose (the highest dose which did not induce any smooth muscle contraction) of capsaicin (10(-8) to 10(-7) M) increased the amplitudes of contractions evoked by electrical field stimulation (EFS) significantly, but not those by acetylcholine (ACh). The inhibitor of neutral endopeptidase, phosphoramidon (10(-7) to 10(-6) M), increased the contractions evoked by EFS significantly. The inhibitor of cholinesterase, physostigmine (10(-6) to 10(-5) M), induced smooth muscle contractions, but such contractions were inhibited by atropine, suggesting the spontaneous release of ACh from the vagal nerve terminals. The subthreshold dose of substance P or capsaicin increased the contractions evoked by physostigmine. These results indicated that endogenous tachykinins increase the spontaneous ACh release as well as the ACh release in response to vagal stimulation from the nerve terminals. Furthermore, it is suggested that the excitatory effects of the tachykinins on the vagal neuro-effector transmission may be modulated by neutral endopeptidase in the guinea pig.

Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.

DTIC Science & Technology

1983-09-30

Pathways; GABAergic Pathway; Atropine; Reserpine; Alphamethylparatyrosine; Oxotremorine ; Feedback 20 ABSTRACT (Continue on reverse side It necessary and...see Preface). The purpose was the compare the regional distribution of the effect of anticholinesterases with oxotremorine ),a selective centrally...hippocampus, differently from oxotremorine which was ineffective. In the other two regions, physostigmine and oxotremorine were equally active. At the

Critical role of CA1 muscarinic receptors on memory acquisition deficit induced by total (TSD) and REM sleep deprivation (RSD).

PubMed

Javad-Moosavi, Bibi-Zahra; Vaezi, Gholamhassan; Nasehi, Mohammad; Haeri-Rouhani, Seyed-Ali; Zarrindast, Mohammad-Reza

2017-10-03

Despite different theories regarding sleep physiological function, an overall census indicates that sleep is useful for neural plasticity which eventually strengthens cognition and brain performance. Different studies show that sleep deprivation (SD) leads to impaired learning and hippocampus dependent memory. According to some studies, cholinergic system plays an important role in sleep (particularly REM sleep), learning, memory, and its retrieval. So this study has been designed to investigate the effect of CA1 Cholinergic Muscarinic Receptors on memory acquisition deficit induced by total sleep deprivation (TSD) and REM sleep deprivation (RSD). A modified water box (locomotor activity may be provide a limiting factor in this method of SD) or multiple platforms were used for induction of TSD or RSD, respectively. Inhibitory passive avoidance apparatus has been used to determine the effects of SD and its changes by physostigmine (as cholinesterase inhibitor) or scopolamine (muscarinic receptor antagonist) on memory formation. Because locomotor activity and pain perception induce critical roles in passive avoidance memory formation, we also measured these factors by open field and hot-plate instruments, respectively. The results showed that TSD and RSD for 24 hours impaired memory formation but they did not alter locomotor activity. TSD also induced analgesia effect, but RSD did not alter it. Intra-CA1 injection of physostigmine (0.0001μg/rat) and scopolamine (0.01μg/rat) did not alter memory acquisition in the sham-TSD or sham-RSD, by themselves. Moreover, intra-CA1 injection of sub-threshold dose of physostigmine (0.0001μg/rat) and scopolamine (0.01μg/rat) could restore the memory acquisition deficit induced by RSD, while scopolamine could restore TSD-induced amnesia. Both drugs reversed analgesia induced by TSD. None of previous interventions altered locomotor activity. According to this study, CA1 cholinergic muscarinic receptors play an important role in amnesia induced by both TSD and RSD. However further studies are needed for showing cellular and molecular mechanisms of surprising result of similar pharmacological effects using compounds with opposite profiles. Copyright © 2016. Published by Elsevier Inc.

The Effects of Pyridostigmine and Physostigmine on the Cholinergic Synapse

DTIC Science & Technology

1984-06-01

patients with neuromuscular disorders, such as myasthenia gravis , or to patients under curaraform neuromuscular blockade. While there is a dirth of...examined due to its widespread use as a therapeutic agent in the management of myasthenia gravis . Short term treatment (up to 7 days) with neostigmine...unique phenomenon since such variation is commonly observed in mammalian INJs affectd by myasthenia gravis (Engel and Santa, 1973), interrupted

Distribution of physostigmine and metabolites in brain subcellular fractions of the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, B.F.; Somani, S.M.

1987-10-26

The distribution of /sup 3/H-physostigmine (Phy) has been studied in the rat brain subcellular fractions at various time intervals following i.v. injection. /sup 3/H-Phy or its metabolites rapidly accumulate into the cytoplasm of cells and penetrates the intracellular compartments. Kinetic studies of the subcellular distribution of radioactivity (RA) per gm of rat brain following i.v. injection of /sup 3/H-Phy show peak concentrations at 30 min in all subcellular fractions with the exception of mitochondria. In the mitochondrial fraction the RA levels continue to rise from 4682 +/- 875 DPM/gm at 5 min to 27,474 +/- 2825 DPM/gm at 60 minmore » (P < .05). The cytosol contains the highest RA: 223,341 +/- 21,044 DPM/gm at 30 min which declined to 53,475 +/- 3756 DPM/gm at 60 min. RA in synaptosome, microsomes and myelin increases from 5 to 30 min, and declines at 60 min. In vitro studies did not show a greater uptake of RA by the mitochondrial or synaptosomal fractions. The finding of relatively high concentrations of RA in the mitochondrial fraction at 60 min increases the likelihood that Phy or its metabolites could interfere with the physiological function of the organelle. 21 references, 1 figure, 2 tables.« less

Imaging changes in synaptic acetylcholine availability in living human subjects

PubMed Central

Esterlis, Irina; Hannestad, Jonas O.; Bois, Frederic; Sewell, R. Andrew; Tyndale, Rachel; Seibyl, John P.; Picciotto, Marina R.; Laruelle, Marc; Carson, Richard E.; Cosgrove, Kelly P.

2013-01-01

Introduction In vivo estimation of beta2-nicotinic acetylcholine receptor (β2*-nAChR) availability with molecular neuroimaging is complicated by competition between the endogenous neurotransmitter ACh and the radioligand [123I]5-IA-85380 ([123I]5-IA). We examined whether binding of [123I]5-IA is sensitive to increases in extracellular levels of ACh in humans, as suggested in non-human primates (1). Methods Six healthy subjects (31±4yrs) participated in one [123I]5-IA SPECT study. After baseline scans, physostigmine (1–1.5mg) was administered IV over 60 min, and additional scans were collected (8–14h). Results We observed a significant reduction in VT/fp (total volume of distribution) after physostigmine (29±17% cortex, 19±15% thalamus, 19±15% striatum, and 36±30% cerebellum; p<.05). This reflected a combination of a region-specific 7–16% decrease in tissue concentration of tracer and 9% increase in plasma parent concentration. Conclusion These data suggest that increases in ACh compete with [123I]5-IA for binding to β2*-nAChRs. Additional validation of this paradigm is warranted, but it may be used to interrogate changes in extracellular ACh. PMID:23160789

A reversed-phase compatible thin-layer chromatography autography for the detection of acetylcholinesterase inhibitors.

PubMed

Ramallo, I Ayelen; García, Paula; Furlan, Ricardo L E

2015-11-01

A dual readout autographic assay to detect acetylcholinesterase inhibitors present in complex matrices adsorbed on reversed-phase or normal-phase thin-layer chromatography plates is described. Enzyme gel entrapment with an amphiphilic copolymer was used for assay development. The effects of substrate and enzyme concentrations, pH, incubation time, and incubation temperature on the sensitivity and the detection limit of the assay were evaluated. Experimental design and response surface methodology were used to optimize conditions with a minimum number of experiments. The assay allowed the detection of 0.01% w/w of physostigmine in both a spiked Sonchus oleraceus L. extract chromatographed on normal phase and a spiked Pimenta racemosa (Mill.) J.W. Moore leaf essential oil chromatographed on reversed phase. Finally, the reversed-phase thin-layer chromatography assay was applied to reveal the presence of an inhibitor in the Cymbopogon citratus (DC.) Stapf essential oil. The developed assay is able to detect acetylcholinesterase inhibitors present in complex matrixes that were chromatographed in normal phase or reversed-phase thin-layer chromatography. The detection limit for physostigmine on both normal and reversed phase was of 1×10(-4) μg. The results can be read by a change in color and/or a change in fluorescence. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Effects of Anticholinesterases and Atropine Derivatives on Visual Function in Human Subjects

DTIC Science & Technology

1988-02-01

preserve life. There is a considerable species difference : for instance, pyridostigmine has practically no protective effect in rats (Gordon et al, 1978...absorption of the drug . This may provide another route, in addition to transcorneal absorption, by which physostigmine evedrops have their central...have been a factor accounting for this difference . In simplifying our results, the term for pupil diameter could reasonably be ignored since its effect

Deanol acetamidobenzoate treatment in choreiform movement disorders.

PubMed

Tarsy, D; Bralower, M

1977-12-01

Deanol acetamidobenzoate was administered in double-blind, crossover fashion with placebo to five patients with tardive dyskinesia, three patients with Huntington's chorea, and one patient with posthemiplegic chorea. No significant effect on dyskinesia was observed. Preliminary administration of physostigmine salicylate to patients with tardive dyskinesia had a variable effect, while benztropine mesylate produced no change. Since the status of deanol as an effective precursor of acetylcholine is uncertain, further trials with putative cholinergic agents remain warranted in choreiform syndromes.

The Anticholinergic and Antiglutamatergic Drug Caramiphen Reduces Seizure Duration in Soman-Exposed Rats: Synergism with the Benzodiazepine Diazepam

DTIC Science & Technology

2012-01-01

progress to self-sustained seizures ( status epilepticus , SE) and result in extensive neuropathology as seen in rats (de Araujo Furtado et al., 2009, 2010...physostigmineOP organophosphorus BuChE butyrylcholinesterase ChE cholinesterase SE status epilepticus ATR atropine sulfate 2-PAM 2-pralidoxime NMDA N...L.C., Lichtenstein, S., Yourick, D.L., 2010. Spontaneous recurrent seizures after status epilepticus induced by soman in Sprague-Dawley rats

Anticholinesterase Effects on Number and Function of Brain Muscarinic Receptors and Central Cholinergic Activity: Drug Intervention.

DTIC Science & Technology

1986-04-11

Leudee NWI 5th England 18. brain;striatum;hippocampus;cortex;brainstem;rat;hydrophilic drugs;hydrophobic drugs; oxotremorine ;physostigmine;choline...challenged with oxotremorine , marked cross-tolerance to the ACh-increasing action f the muscarinic receptor agonist was induced in both striatum and...responses except for slight tremor.A Fig. 2 shows the dose-response curves of the muscarinic agonists oxotremorine and the butynyl base, McN-A-343, a

Hepatic and muscle clearance of physostigmine in the rat after i. v. administration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Somani, S.M.; Unni, L.K.

1986-03-01

This study presents a method to calculate the extraction ratio (ER) from in vivo time course of liver metabolism using the physiological and pharmacokinetic parameters such as plasma flow rate, partition coefficient of drug between tissue and plasma and the elimination rate constant from tissues. Rats were administered /sup 3/H-physostigmine (Phy), 100 ..mu..g/kg i.v.; and were sacrificed at various times. Tissues were removed and Phy and its metabolites were determined by HPLC. Half-life of Phy in liver and muscle was 24 and 20 min, respectively. ER of Phy in liver was .71 which showed a slight decrease at 10 min.more » Muscle ER was found to be .347 up to 5 min. Hepatic clearance was calculated to be 23.08 ml/min/kg (34.9% of systemic clearance) and the intrinsic clearance was 83.73 ml/min/kg which indicates that the changes in blood flow to the liver can cause a variation in the systematic clearance. Percentage dose of Phy retained in muscle was maximum and the clearance was 5.2 ml/min/kg suggesting that muscle might be acting as a storage depot for Phy prolonging the pharmacological effects. About 30-40% of radioactivity in the liver could not be washed off by 10% TCA or organic solvents indicating the irreversible binding of drug or metabolite to liver macromolecule.« less

Deadly nightshade (Atropa belladonna) intoxication: an analysis of 49 children.

PubMed

Caksen, Hüseyin; Odabaş, Dursun; Akbayram, Sinan; Cesur, Yaşar; Arslan, Sükrü; Uner, Abdurrahman; Oner, Ahmet Faik

2003-12-01

Deadly nightshade (Atropa belladonna) intoxication has been infrequently reported in both children and adults in the literature. In this article, the clinical and laboratory findings of 49 children with acute deadly nightshade intoxication are reviewed. Our purpose was to enlighten the findings of deadly nightshade intoxication in childhood. The most common observed symptoms and signs were meaningless speech, tachycardia, mydriasis, and flushing. None of the children required mechanical ventilation or died in our series. The patients were categorized into two groups, mild/moderate and severe intoxication. Children with and without encephalopathy were accepted as severe and mild/moderate intoxication, respectively. While 43 children were placed in the group of mild/moderate intoxication, six were in severe intoxication group. We found that meaningless speech, lethargy, and coma were more common, but tachycardia was less common in the severe intoxication group (children with encephalopathy) (P < 0.05). In the treatment, neostigmine was used in all children because of no available physostigmine in our country. In conclusion, our findings showed that the initial signs and symptoms of acute deadly nightshade intoxication might be severe in some children, but no permanent sequel and death were seen in children. We also showed that meaningless speech, lethargy, coma, and absence of tachycardia were ominous signs in deadly nightshade intoxication in childhood. Lastly, we suggest that neostigmine may be used in cases of deadly nightshade intoxication if physostigmine cannot be available.

The effect of drugs acting on cholinoceptors and mucosal chloride on luminal bicarbonate transport by rat caecum under in vitro conditions.

PubMed Central

Canfield, P.; Abdul-Ghaffar, T.

1991-01-01

1. The transport of HCO3- (Jsm) from a HCO3(-)-buffered serosal to an unbuffered mucosal saline solution has been studied in rat caecum in vitro. 2. Carbachol, bethanechol and acetylcholine (ACh) caused a concentration-dependent fall in Jsm with similar maximum effects. 1,1-Dimethyl-4-phenyl-piperazinium iodide (DMPP) also inhibited Jsm but the effect was less than with the other drugs. Maximum cholinoceptor inhibition was less than that obtained with anoxia. 3. Responses were blocked by atropine (10(-5) M) but hexamethonium (2 x 10(-4) M) significantly altered the response only to DMPP. 4. Physostigmine (10(-5) M) shifted the ACh response curve to the left but physostigmine itself caused inhibition of Jsm which was blocked by atropine. 5. Substitution of mucosal Cl- by NO3- reduced Jsm to a similar extent to maximum cholinoceptor effect and abolished responses to bethanecol. Anoxia further reduced Jsm in the presence of NO3-. 6. Mucosal SITS and DIDS (1 mM) reduced Jsm but this was less than the maximum inhibition seen with drugs acting on cholinoceptors or mucosal Cl- removal. Serosal DIDS caused a similar inhibition. 7. We conclude that cholinoceptor agonists inhibit but do not abolish luminal bicarbonate transport by an action on muscarinic receptors. PMID:1884114

IMMEDIATE EFFECTS OF X-IRRADIATION ON THE HEART OF THE FROG

DOE Office of Scientific and Technical Information (OSTI.GOV)

Onkelinx, Cl.

1962-07-21

The effects of whole-body irradiations on the heartbeat of pithed frogs were studied. A strong bradycardia was observed after 1 to 5 min of irradiation and is reversible within 1 min after irradiation. A sino-auricular block was observed in some cases. No response was found in any of the frogs during the cold months. The effects of atropine, physostigmine, and eserine on the response were studied. The results suggest a vagal excitation or acetylcholine liberation from the irradiation. (D.L.C.)

The Effects of Exercise on Pharmacokinetics and Pharmacodynamics of Physostigmine in Rats

DTIC Science & Technology

1991-02-15

combination of the two, regulate the biosynthetic and degradative enzymes of ACh in EDL (extensor digitorum longus) - fast muscle and soleus - slow muscle...and trained exercise on ChAT activities in fast and slow muscles of rat 100 17. Effect of subacute Phy (70 4g/kg, i.m.) and endurance training on...AChE activities in EDL and soleus muscles of rat 100 18. ChAT and AChE activities (% of control) in fast (EDL) and slow (soleus) muscle in subacute Phy

The Effects of Exercise on Pharmacokinetics and Pharmacodynamics of Physostigmine in Rats

DTIC Science & Technology

1989-02-15

Phy ( cholinesterase activity ) are likely to be altered by exercise due to altered blood flow rates to liver and pH of muscle. During exercise...concurrent acute exercise on the ChE activity in RBC aad tissues and in blood biochemical parameters in rats. Phy has been reported to reduce the...Springfield, Illinois. Also, we have studied the effect of exercise training, Phy and training + Phy on ChE activity in RBC and tissues and on blood biochemi

Kinetics and metabolism of physostigmine in rat in the presence of soman

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khalique, A.; Somani, S.M.

1986-03-01

The effect of soman (105 ..mu..g/kg; 1.5 LD/sub 50/ s.c.) administration on pharmacokinetics and metabolism of /sup 3/H-physostigmine (Phy) was studied in rats. The rats were pretreated with either Phy 100 ..mu..g/kg i.v. or 500 ..mu..g/kg i.m., 5 or 15 min prior to soman administration. Phy and metabolites were determined in plasma and brain by HPLC. The half-life of Phy in plasma after i.v. administration was 15.5 min both in the presence and absence of soman, however the t/sub 1/2/ in brain was 11 min and 13 min, respectively. Clearance was 71.4 ml/min/kg in the Phy treated rat and 90more » ml/min/kg in the presence of soman. The half-life of Phy in plasma was 18 min and 17 min, and in brain 17 min and 15 min, respectively in the absence and presence of soman after i.m. dose of Phy. Clearance after Phy treatment was 85.2 mlmin/kg however in the presence of soman, it was 66.7 ml/min/kg. Phy was slightly less metabolized to eseroline and two other metabolites, M/sub 1/ and M/sub 2/, in the presence of soman after i.v. as well as after i.m. administration in plasma and brain. The soman administration does not change the pharmacokinetics of Phy by the two different dosages and routes of administration.« less

Stimulation by atropine of acetylcholine release and synthesis in cortical slices from rat brain

PubMed Central

Molenaar, P. C.; Polak, R. L.

1970-01-01

1. Cortical slices from rat brain were incubated in media containing the irreversible cholinesterase inhibitor soman and a high KCl concentration, and the release and synthesis of acetylcholine (ACh) were determined. 2. Atropine enhanced the release and synthesis of ACh. 3. Tetrodotoxin, a substance which blocks nervous conduction, did not influence the release and synthesis of ACh, in the absence or in the presence of atropine. Therefore the nerve endings are probably the site at which atropine acts when stimulating the release and synthesis of ACh. 4. Pretreatment of the slices with botulinum type A toxin partially blocked the release and synthesis of ACh and reduced the extra amounts of ACh released and synthesized under the influence of atropine. 5. Lowering the calcium or raising the magnesium concentration in the incubation medium reduced the release and synthesis of ACh and their enhancement by atropine. 6. Physostigmine decreased the total extractable ACh content of the slices during incubation in a 25 mM KCl containing medium. This decrease was nearly prevented when the release and synthesis of ACh were inhibited by omission of the calcium ions from the medium, but was enhanced by atropine. 7. The observations made with pretreatment by botulinum type A toxin, with changes in the calcium and magnesium concentration as well as with physostigmine, all support the theory that it is primarily the release of ACh which is enhanced by atropine and that its stimulating action on the synthesis results from the increased release. PMID:5497792

Pharmacological treatments of cerebellar ataxia.

PubMed

Ogawa, Masafumi

2004-01-01

The confirmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic symptoms are reviewed. Previous studies showed some efficacy of physostigmine in ataxic patients. However, physostigmine did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not definitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study, buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect.

Postoperative Anticholinergic Poisoning: Concealed Complications of a Commonly Used Medication.

PubMed

Zhang, Xiao Chi; Farrell, Natalija; Haronian, Thomas; Hack, Jason

2017-10-01

Scopolamine is a potent anticholinergic compound used commonly for the prevention of postoperative nausea and vomiting. Scopolamine can cause atypical anticholinergic syndromes due to its prominent central antimuscarinic effects. A 47-year-old female presented to the emergency department (ED) 20 h after hospital discharge for a right-knee meniscectomy, with altered mental status (AMS) and dystonic extremity movements that began 12 h after her procedure. Her vital signs were normal and physical examination revealed mydriasis, visual hallucinations, hyperreflexia, and dystonic movements. Laboratory data, lumbar puncture, and computed tomography were unrevealing. The sustained AMS prompted a re-evaluation that revealed urinary overflow with 500 mL of retained urine discovered on ultrasound and a scopolamine patch hidden behind her ear. Her mental status improved shortly after patch removal and physostigmine, with complete resolution after 24 h with discharge diagnosis of scopolamine-induced anticholinergic toxicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although therapeutically dosed scopolamine transdermal patches rarely cause complications, incomplete toxidromes can be insidiously common in polypharmacy settings. Providers should thoroughly evaluate the skin of intoxicated patients for additional adherent medications that may result in a delay in ED diagnosis and curative therapies. Our case, as well as rare case reports of therapeutic scopolamine-induced anticholinergic toxicity, demonstrates that peripheral anticholinergic effects, such as tachycardia, dry mucous membranes, and hyperpyrexia are often not present, and incremental doses of physostigmine may be required to reverse scopolamine's long duration of action. This further complicates identification of the anticholinergic toxidrome and diagnosis. Published by Elsevier Inc.

Cholinergic and ghrelinergic receptors and KCNQ channels in the medial PFC regulate the expression of palatability.

PubMed

Parent, Marc A; Amarante, Linda M; Swanson, Kyra; Laubach, Mark

2015-01-01

The medial prefrontal cortex (mPFC) is a key brain region for the control of consummatory behavior. Neuronal activity in this area is modulated when rats initiate consummatory licking and reversible inactivations eliminate reward contrast effects and reduce a measure of palatability, the duration of licking bouts. Together, these data suggest the hypothesis that rhythmic neuronal activity in the mPFC is crucial for the control of consummatory behavior. The muscarinic cholinergic system is known to regulate membrane excitability and control low-frequency rhythmic activity in the mPFC. Muscarinic receptors (mAChRs) act through KCNQ (Kv7) potassium channels, which have recently been linked to the orexigenic peptide ghrelin. To understand if drugs that act on KCNQ channels within the mPFC have effects on consummatory behavior, we made infusions of several muscarinic drugs (scopolamine, oxotremorine, physostigmine), the KCNQ channel blocker XE-991, and ghrelin into the mPFC and evaluated their effects on consummatory behavior. A consistent finding across all drugs was an effect on the duration of licking bouts when animals consume solutions with a relatively high concentration of sucrose. The muscarinic antagonist scopolamine reduced bout durations, both systemically and intra-cortically. By contrast, the muscarinic agonist oxotremorine, the cholinesterase inhibitor physostigmine, the KCNQ channel blocker XE-991, and ghrelin all increased the durations of licking bouts when infused into the mPFC. Our findings suggest that cholinergic and ghrelinergic signaling in the mPFC, acting through KCNQ channels, regulates the expression of palatability.

Assessment of anti-cholinesterase activity and cytotoxicity of cagaita (Eugenia dysenterica) leaves.

PubMed

Gasca, Cristian A; Castillo, Willian O; Takahashi, Catarina Satie; Fagg, Christopher W; Magalhães, Pérola O; Fonseca-Bazzo, Yris M; Silveira, Dâmaris

2017-11-01

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 1 H and 13 C NMR. The IC 50 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 50 value of 155.20 ± 2.09 μg/ml. Physostigmine, quercetin, and catechin showed IC 50 values of 18.69 ± 0.07, 46.59 ± 0.49, and 42.39 ± 0.67 μg/ml, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

Screening for Developmental Neurotoxicity Using PC12 Cells: Comparisons of Organophosphates with a Carbamate, an Organochlorine, and Divalent Nickel

PubMed Central

Slotkin, Theodore A.; MacKillop, Emiko A.; Ryde, Ian T.; Tate, Charlotte A.; Seidler, Frederic J.

2007-01-01

Background In light of the large number of chemicals that are potential developmental neurotoxicants, there is a need to develop rapid screening techniques. Objectives We exposed undifferentiated and differentiating neuronotypic PC12 cells to different organophosphates (chlorpyrifos, diazinon, parathion), a carbamate (physostigmine), an organochlorine (dieldrin), and a metal (divalent nickel; Ni2+) and examined indices of cell replication and differentiation for both short- and long-term exposures. Results In undifferentiated cells, all the agents inhibited DNA synthesis, with the greatest effect for diazinon, but physostigmine eventually produced the largest deficits in the total number of cells after prolonged exposure. The onset of differentiation intensified the adverse effects on DNA synthesis and changed the rank order in keeping with a shift away from noncholinergic mechanisms and toward cholinergic mechanisms. Differentiation also worsened the effects of each agent on cell number after prolonged exposure, whereas cell growth was not suppressed, nor were there any effects on viability as assessed with trypan blue. Nevertheless, differentiating cells displayed signs of oxidative stress from all of the test compounds except Ni2+, as evidenced by measurements of lipid peroxidation. Finally, all of the toxicants shifted the transmitter fate of the cells away from the cholinergic phenotype and toward the catecholaminergic phenotype. Conclusions These studies point out the feasibility of developing cell-based screening methods that enable the detection of multiple end points that may relate to mechanisms associated with developmental neurotoxicity, revealing some common targets for disparate agents. PMID:17366826

Time course of cholinesterase activity in plasma, brain and muscle of rat pretreated with physostigmine, and then soman

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giacobini, E.; Boyer, A.; Somani, S.M.

1986-03-05

Time course of /sup 3/H-physostigmine (Phy) concentration and cholinesterase (ChE) activity in plasma and tissues was studied in rats pretreated with Phy and then soman. Rats were dosed with Phy (100 ..mu..g/kg, i.v.), 5 or 15 min prior to soman (105 ..mu..g/kg, 1.5 LD/sub 50/, s.c.) treatment and were sacrificed at various times; Phys conc. and ChE activity were determined. BuChE activity in plasma was 5% of control from 7-30 min after Phy i.v. pretreatment and soman or soman alone treatment. Plasma Phy conc. steadily declined (32.6 ng/ml at 7 min) to 15 ng/ml at 30 min. ChE activity inmore » muscle was 60-50% of control for Phy pretreated but soman alone gave 85-72% activity from 2-30 min. Brain ChE activity was about 5% of control within 2 min after soman treatment; however, with Phy pretreatment, the activity was about 52% at 7 min, 40% at 22 min, which recovered to 45% of control at 35 min, indicating that Phy protected brain ChE. Brain Phy conc. steadily declined (58.6 ng/g at 7 min) to 11.7 ng/g at 30 min. However, pretreatment of rat with a higher dose of Phy and then soman showed BuChE in plasma and ChE in brain and muscle to be about 25, 35 and 51%, in comparison to about 5% in plasma and brain with soman alone treatment, indicating higher protection of ChE enzyme with higher conc. of Phy in plasma and brain.« less

Protection against diisopropylfluorophosphate intoxication by pyridostigmine and physostigmine in combination with atropine and mecamylamine.

PubMed

Harris, L; Stitcher, D

1984-08-01

Atropine (A), mecamylamine (M), pyridostigmine (Py) and physostigmine (Ph) are pretreatment components of Mix I (A = 0.79, M = 0.79, Py = 0.056 mg/kg) and Mix II (A = 0.79, M = 0.79, Ph = 0.026 mg/kg). They have been successfully used in antagonizing Soman intoxication in experimental animals. Rats were pretreated with either Mix I or Mix II and subsequently exposed to diisopropylfluorphosphate (DFP). Pretreatment with Mix I or Mix II (i.m.) 30 min before DFP (i.v.) protected rats from the lethal effects of DFP. The protective ratios were 2.8 (Mix I) and 6.9 (Mix II). Changes in brain levels of acetylcholine (ACh) were measured to help understand the basis for effectiveness of these pretreatments. In the absence of DFP, pretreatments had no significant (P greater than 0.05) effect on bound or free ACh. Pretreatment did not prevent the DFP-induced rise in bound and free ACh nor the agent-induced physical incapacitation at 30 min post exposure. At 2 h after DFP exposure, rats pretreated with Mix II, but not Mix I, showed significant recovery from signs of physical incapacitation. At 30 min after the administration of 3.3 mg/kg of DFP (i.v.), the levels of free and bound ACh in rats given Mix I or Mix II pretreatment increased above control levels by 705% and 116% and 120% and 43%, respectively. By 2 h after DFP, cerebral ACh levels had changed to 437% and 91% with Mix I pretreatment and 26% and 50% with Mix II pretreatment. These data suggest a correlation between DFP-induced increases in the levels of cerebral ACh, possibly free, and physical incapacitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.

PubMed

Mineur, Yann S; Bentham, Matthew P; Zhou, Wen-Liang; Plantenga, Margreet E; McKee, Sherry A; Picciotto, Marina R

2015-10-01

The a2A-noradrenergic agonist guanfacine can decreases stress-induced smoking in female, but not male, human smokers. It is not known whether these effects are due to effects on mood regulation and/or result from nicotinic-cholinergic interactions. The objective of the study was to determine whether there are sex differences in the effect of guanfacine in tests of anxiolytic and antidepressant efficacy in mice at baseline and in a hypercholinergic model of depression induced by the acetylcholinesterase inhibitor physostigmine. The effects of guanfacine were measured in the light/dark box, tail suspension, and the forced swim test in female and male C57BL/6J mice. In parallel, electrophysiological properties were evaluated in the prefrontal cortex, a critical brain region involved in stress responses. c-fos immunoreactivity was measured in other brain regions known to regulate mood. Despite a baseline sex difference in behavior in the forced swim test (female mice were more immobile), guanfacine had similar, dose-dependent, antidepressant-like effects in mice of both sexes (optimal dose, 0.15 mg/kg). An antidepressant-like effect of guanfacine was also observed following pre-treatment with physostigmine. A sex difference in the paired-pulse ratio in the prefrontal cortex (PFC) (male, 1.4; female, 2.1) was observed at baseline that was normalized by guanfacine. Other brain areas involved in cholinergic control of depression-like behaviors, including the basolateral amygdala and lateral septum, showed sex-specific changes in c-fos expression. Guanfacine has a robust antidepressant-like effect and can reverse a depression-like state induced by increased acetylcholine (ACh) signaling. These data suggest that different brain areas are recruited in female and male mice, despite similar behavioral responses to guanfacine.

Amyloid Precursor Protein 96–110 and β-Amyloid 1–42 Elicit Developmental Anomalies in Sea Urchin Embryos and Larvae that are Alleviated by Neurotransmitter Analogs for Acetylcholine, Serotonin and Cannabinoids

PubMed Central

Buznikov, Gennady A.; Nikitina, Lyudmila A.; Seidler, Frederic J.; Slotkin, Theodore A.; Bezuglov, Vladimir V.; Milošević, Ivan; Lazarević, Lidija; Rogač, Ljubica; Ruzdijić, Sabera; Rakić, Ljubiša M.

2008-01-01

Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96–110, play an important role in neurite outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP96–110 in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of β-amyloid 1–42 (Aβ42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer’s Disease. Although both peptides elicited dysmorphogenesis, Aβ42 was far more potent; in addition, whereas Aβ42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP96–110 effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or α-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer’s Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, α-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain. PMID:18565728

Long-acting anticholinesterases for myasthenia gravis: synthesis and activities of quaternary phenylcarbamates of neostigmine, pyridostigmine and physostigmine

PubMed Central

Yu, Qian-sheng; Holloway, Harold W.; Luo, Weiming; Lahiri, Debomoy K.; Brossi, Arnold; Greig, Nigel H.

2010-01-01

The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (−)-phenserine (12), (−)-tolserine (14), (−)-cymserine (16) and (−)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5–8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis. PMID:20627738

Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand 18F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys.

PubMed

Gallezot, Jean-Dominique; Esterlis, Irina; Bois, Frederic; Zheng, Ming-Qiang; Lin, Shu-Fei; Kloczynski, Tracy; Krystal, John H; Huang, Yiyun; Sabri, Osama; Carson, Richard E; Cosgrove, Kelly P

2014-11-01

18F-(-)-NCFHEB (also known as 18F-(-)-Flubatine) is a new radioligand to image α4β2* nicotinic acetylcholine receptors in vivo with positron emission tomography (PET), with faster kinetics than previous radioligands such as 18F-2-F-A85380. The goal of this study was to assess the sensitivity of 18F-(-)-NCFHEB-PET to increases in synaptic acetylcholine concentration induced by acetylcholinesterase inhibitors. Two rhesus monkeys were scanned four times each on a Focus 220 scanner: first at baseline, then during two bolus plus infusions of physostigmine (0.06-0.28 mg/kg), and finally following a bolus injection of donepezil (0.25 mg/kg). The arterial input function and the plasma free fraction fP were measured. 18F-(-)-NCFHEB volume of distribution VT was estimated using the multilinear analysis MA1 and then normalized by plasma free fraction fP . 18F-(-)-NCFHEB fP was 0.89±0.04. At baseline, 18F-(-)-NCFHEB VT /fP ranged from 7.9±1.3 mL plasma/cm3 tissue in the cerebellum to 34.3±8.4 mL plasma/cm3 tissue in the thalamus. Physostigmine induced a dose-dependent reduction of 18F-(-)-NCFHEB VT /fP of 34±9% in the putamen, 32±8% in the thalamus, 25±8% in the cortex, and 23±10% in the hippocampus. With donepezil, 18F-(-)-NCFHEB VT /fP was reduced by 24±2%, 14+3% and 14±5%, 10±6% in the same regions. 18F-(-)-NCFHEB can be used to detect changes in synaptic acetylcholine concentration and is a promising tracer to study acetylcholine dynamics with shorter scan durations than previous radioligands. © 2014 Wiley Periodicals, Inc.

Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention.

PubMed

Ricciardi, Emiliano; Handjaras, Giacomo; Bernardi, Giulio; Pietrini, Pietro; Furey, Maura L

2013-01-01

Enhancing cholinergic function improves performance on various cognitive tasks and alters neural responses in task specific brain regions. We have hypothesized that the changes in neural activity observed during increased cholinergic function reflect an increase in neural efficiency that leads to improved task performance. The current study tested this hypothesis by assessing neural efficiency based on cholinergically-mediated effects on regional brain connectivity and BOLD signal variability. Nine subjects participated in a double-blind, placebo-controlled crossover fMRI study. Following an infusion of physostigmine (1 mg/h) or placebo, echo-planar imaging (EPI) was conducted as participants performed a selective attention task. During the task, two images comprised of superimposed pictures of faces and houses were presented. Subjects were instructed periodically to shift their attention from one stimulus component to the other and to perform a matching task using hand held response buttons. A control condition included phase-scrambled images of superimposed faces and houses that were presented in the same temporal and spatial manner as the attention task; participants were instructed to perform a matching task. Cholinergic enhancement improved performance during the selective attention task, with no change during the control task. Functional connectivity analyses showed that the strength of connectivity between ventral visual processing areas and task-related occipital, parietal and prefrontal regions reduced significantly during cholinergic enhancement, exclusively during the selective attention task. Physostigmine administration also reduced BOLD signal temporal variability relative to placebo throughout temporal and occipital visual processing areas, again during the selective attention task only. Together with the observed behavioral improvement, the decreases in connectivity strength throughout task-relevant regions and BOLD variability within stimulus processing regions support the hypothesis that cholinergic augmentation results in enhanced neural efficiency. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effects of (-)-S-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate monohydrate (YM796), a novel muscarinic agonist, on disturbance of passive avoidance learning behavior in drug-treated and senescence-accelerated mice.

PubMed

Suzuki, M; Yamaguchi, T; Ozawa, Y; Ohyama, M; Yamamoto, M

1995-11-01

Effects of YM796 (-)-S-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate monohydrate; a novel muscarinic agonist, were observed on disturbance of passive avoidance learning behavior in drug- (protein synthesis inhibitor and anticholinergic drugs) treated and senescence-accelerated mice in comparison with those of a muscarinic agonist (AF102B) and acetylcholinesterase inhibitors (E2020 (1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-yl) methyl] piperidene hydrochloride), NIK247 [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate hydrochloride], THA (9-amino-1,2,3,4-tetrahydroacridine) and physostigmine). All tested drugs administered before training significantly prolonged the shortened latency of step-through induced by the protein synthesis inhibitor cycloheximide (150 mg/kg s.c.). This shortened latency was also significantly prolonged when YM796 was administered immediately after training, but not when administered before the test trial. The ameliorating effect of YM796 on the impairment in learning behavior by cycloheximide was significantly suppressed by pirenzepine (0.1 micrograms/mouse i.c.v.). When administered before training, all test drugs prolonged the shortened latency of step-through induced by treatment with the anticholinergic drugs [scopolamine (1 mg/kg s.c.) and hemicholinium-3 (0.3 microgram/mouse i.c.v.)], suggesting that they ameliorated the impairment of learning behavior. This shortened latency in scopolamine-treated mice was also significantly prolonged by YM796, AF102B, E2020, NIK247 and physostigmine when administered immediately after training, but not when administered before the test trial. The pharmacological actions of YM796 administered immediately after training and before the test trial in hemicholinium-3-treated mice were similar to those in scopolamine-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Geissoschizine methyl ether, a corynanthean-type indole alkaloid from Uncaria rhynchophylla as a potential acetylcholinesterase inhibitor.

PubMed

Yang, Zhong-Duo; Duan, Dong-Zhu; Du, Juan; Yang, Ming-Jun; Li, Shuo; Yao, Xiao-Jun

2012-01-01

Geissoschizine methyl ether (1), a newly discovered strong acetylcholinesterase (AChE) inhibitor, along with six weakly active alkaloids, vallesiachotamine (2), hisuteine (3), hirsutine (4), isorhynchophylline (5), cisocorynoxeine (6) and corynoxeine (7) have been isolated from Uncaria rhynchophylla. Geissoschizine methyl ether (1) inhibited 50% of AChE activity at concentrations of 3.7 ± 0.3 µg mL(-1) while the IC(50) value of physostigmine as a standard was 0.013 ± 0.002 µg mL(-1). The mode of AChE inhibition by 1 was reversible and non-competitive. In addition, molecular modelling was performed to explore the binding mode of inhibitor 1 at the active site of AChE.

Atropa belladonna intoxication: a case report.

PubMed

Berdai, Mohamed Adnane; Labib, Smael; Chetouani, Khadija; Harandou, Mustapha

2012-01-01

Atropa belladonna is a poisonous plant also called deadly nightshade. Its roots, leaves and fruits contain alkaloids: atropine, hyocyamine and scopolamine. The risk of poisoning in children is important because of possible confusion with other berries. Atropa belladonna acute intoxication is a severe condition, it's should be considered in the presence of anti-cholinergic toxidrome, the differential diagnosis include other plants or psychoactive drugs containing atropine. The treatment is mainly symptomatic including gastrointestinal decontamination with activated charcoal. In severe cases, physostigmine can be used as an antidote. We report the case of 11 year old girl with Atropa belladonna poisoning which was administrated in a therapeutic purpose as a remedy to jaundice. The child presented essentially a central anti-cholinergic syndrome. She was admitted in the intensive care unit, the progression was favorable with symptomatic treatment.

Synthesis, characterization and cholinesterase enzymes inhibitory activity of 1-[3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-4,5-dihydro-pyrazol-1-yl]-ethanone

NASA Astrophysics Data System (ADS)

Mehdi, Sayed Hasan; Ghalib, Raza Murad; Hashim, Rokiah; da Silva, M. Fátima C. Guedes; Sulaiman, Othman; Murugaiyah, Vikneswaran; Marimuthu, Mani Maran; Naqvi, Mehnaz

2013-10-01

The crystal structure of the title compound, 1-[3-methyl-5-(2,6,6-trimethyl-cyclohex-1-enyl)-4,5-dihydro-pyrazol-1-yl]-ethanone has been determined by single crystal X-ray diffraction. It crystallizes in the orthorhombic space group P212121. The FTIR as well as the 1H and 13C NMR spectra of the compound were also recorded and briefly discussed. Compound 1 demonstrated good inhibitory activity against butyrylcholinesterase (BChE; IC50 = 46.42 μM) comparable to physostigmine. However it showed moderate inhibitory activity against acetylcholinesterase (AChE; IC50 = 157.31 μM). It showed moderate inhibitory activity against acetylcholinesterase and selective inhibitory activity towards butyrylcholinesterase enzyme.

Acetylcholine and choline in cerebrospinal fluid of patients with Parkinson's disease and Huntington's chorea.

PubMed Central

Welch, M J; Markham, C H; Jenden, D J

1976-01-01

Lumbar cerebrospinal fluid (CSF) acetylcholine (ACh) and choline (Ch) levels were measured in patients with Huntington's chorea (N=11), Parkinson's disease (N=8), and subjects at risk for Huntington's chorea (N=4), and all three groups were found not to differ significantly from normal controls (N=10). The values found for lumbar CSF ACh and Ch levels in the normal subjects were comparable with previously reported values. The use of physostigmine, a cholinesterase inhibitor, in collecting the CSF samples did not appear to make a difference with regard to ACh and Ch concentrations. Evidence suggesting a ventricular-lumbar gradient, with lumbar CSF Ch concentration being less than ventricular CSF Ch concentration, was found. Finally, ACh levels in CSF did not correlate with corresponding Ch levels. PMID:132512

Ibogaine and the inhibition of acetylcholinesterase.

PubMed

Alper, Kenneth; Reith, Maarten E A; Sershen, Henry

2012-02-15

Ibogaine is a psychoactive monoterpine indole alkaloid extracted from the root bark of Tabernanthe iboga Baill. that is used globally in medical and nonmedical settings to treat drug and alcohol addiction, and is of interest as an ethnopharmacological prototype for experimental investigation and pharmaceutical development. The question of whether ibogaine inhibits acetylcholinesterase (AChE) is of pharmacological and toxicological significance. AChE activity was evaluated utilizing reaction with Ellman's reagent with physostigmine as a control. Ibogaine inhibited AChE with an IC(50) of 520±40 μM. Ibogaine's inhibition of AChE is physiologically negligible, and does not appear to account for observations of functional effects in animals and humans that might otherwise suggest the possible involvement of pathways linked to muscarinic acetylcholine transmission. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schultz, M.K.; Wright, L.K.M.; Stone, M.F.

2012-03-15

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA{sub A}) receptors. However, seizure activity itself causes the endocytosis of GABA{sub A} receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20 mg/kg, im) and DZP (10 mg/kg, sc), administered both separately and in combination, at 10, 20 or 30 min followingmore » seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD{sub 50}; 132 μg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2 mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20–30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity. -- Highlights: ► Soman (GD) produced seizure activity resulting in neuropathology in rats. ► Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ► CED/DZP showed superior anticonvulsant and neuroprotective capacity. ► Physostigmine (PHY) was examined as an adjunct post-exposure therapy. ► PHY attenuated GD-induced seizure development, but not seizure duration.« less

Selective effects of cholinergic modulation on task performance during selective attention.

PubMed

Furey, Maura L; Pietrini, Pietro; Haxby, James V; Drevets, Wayne C

2008-03-01

The cholinergic neurotransmitter system is critically linked to cognitive functions including attention. The current studies were designed to evaluate the effect of a cholinergic agonist and an antagonist on performance during a selective visual attention task where the inherent salience of attended/unattended stimuli was modulated. Two randomized, placebo-controlled, crossover studies were performed, one (n=9) with the anticholinesterase physostigmine (1.0 mg/h), and the other (n=30) with the anticholinergic scopolamine (0.4 mc/kg). During the task, two double-exposure pictures of faces and houses were presented side by side. Subjects were cued to attend to either the face or the house component of the stimuli, and were instructed to perform a matching task with the two exemplars from the attended category. The cue changed every 4-7 trials to instruct subjects to shift attention from one stimulus component to the other. During placebo in both studies, reaction time (RT) associated with the first trial following a cued shift in attention was longer than RT associated with later trials (p<0.05); RT also was significantly longer when attending to houses than to faces (p<0.05). Physostigmine decreased RT relative to placebo preferentially during trials greater than one (p<0.05), with no change during trial one; and decreased RT preferentially during the attention to houses condition (p<0.05) vs attention to faces. Scopolamine increased RT relative to placebo selectively during trials greater than one (p<0.05), and preferentially increased RT during the attention to faces condition (p<0.05). The results suggest that enhancement or impairment of cholinergic activity preferentially influences the maintenance of selective attention (ie trials greater than 1). Moreover, effects of cholinergic manipulation depend on the selective attention condition (ie faces vs houses), which may suggest that cholinergic activity interacts with stimulus salience. The findings are discussed within the context of the role of acetylcholine both in stimulus processing and stimulus salience, and in establishing attention biases through top-down and bottom-up mechanisms of attention.

Selective Effects of Cholinergic Modulation on Task Performance during Selective Attention

PubMed Central

Furey, Maura L; Pietrini, Pietro; Haxby, James V; Drevets, Wayne C

2010-01-01

The cholinergic neurotransmitter system is critically linked to cognitive functions including attention. The current studies were designed to evaluate the effect of a cholinergic agonist and an antagonist on performance during a selective visual attention task where the inherent salience of attended/unattended stimuli was modulated. Two randomized, placebo-controlled, crossover studies were performed, one (n = 9) with the anticholinesterase physostigmine (1.0 mg/h), and the other (n = 30) with the anticholinergic scopolamine (0.4 mc/kg). During the task, two double-exposure pictures of faces and houses were presented side by side. Subjects were cued to attend to either the face or the house component of the stimuli, and were instructed to perform a matching task with the two exemplars from the attended category. The cue changed every 4–7 trials to instruct subjects to shift attention from one stimulus component to the other. During placebo in both studies, reaction time (RT) associated with the first trial following a cued shift in attention was longer than RT associated with later trials (p<0.05); RT also was significantly longer when attending to houses than to faces (p<0.05). Physostigmine decreased RT relative to placebo preferentially during trials greater than one (p<0.05), with no change during trial one; and decreased RT preferentially during the attention to houses condition (p<0.05) vs attention to faces. Scopolamine increased RT relative to placebo selectively during trials greater than one (p<0.05), and preferentially increased RT during the attention to faces condition (p<0.05). The results suggest that enhancement or impairment of cholinergic activity preferentially influences the maintenance of selective attention (ie trials greater than 1). Moreover, effects of cholinergic manipulation depend on the selective attention condition (ie faces vs houses), which may suggest that cholinergic activity interacts with stimulus salience. The findings are discussed within the context of the role of acetylcholine both in stimulus processing and stimulus salience, and in establishing attention biases through top-down and bottom-up mechanisms of attention. PMID:17534379

Effects of subacute pretreatment with carbamate together with acute adjunct pretreatment against nerve agent exposure. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, D.R.; Harris, L.W.; Lennox, W.J.

1991-12-31

Acute carbamate pretreatment, in conjunction with atropine pretreatment or followed by atropine and oxime therapy has been shown to protect rabbits, rats, guinea pigs and monkeys against multiple lethal doses of soman. In those experiments, pretreated animals were usually challenged with soman at the time of peak whole blood acetylcholinesterase (AChE) inhibition by the carbamate or when the concentration of carbamate in the blood was expected to be rapidly diminishing. However, soldiers in a chemical environment, having taken carbamate orally might well be exposed to nerve agent shortly thereafter. Thus, both active carbamate and nerve agent would be entering themore » blood simultaneously. In a recent study it was reported that subacute administration of physostigmine (Phy), via subcutaneously implanted 28 day osmotic minipump, afforded protection against an iv challenge of soman on the 27th day.« less

Cholinergic neurotransmission seems not to be involved in depression but possibly in personality.

PubMed Central

Fritze, J; Lanczik, M; Sofic, E; Struck, M; Riederer, P

1995-01-01

Concordant with the adrenergic-cholinergic imbalance hypothesis of affective psychosis, there is a cholinergic supersensitivity in depression. Thus, the anticholinergic properties of some antidepressants might contribute to their efficacy. However, in the present double-blind studies (n = 20) with mianserin and viloxazine, respectively, which lack anticholinergic properties, adjunctive treatment with the anticholinergic biperiden versus placebo did not enhance the antidepressive efficacy. Therefore, we hypothesized that cholinergic supersensitivity might be linked to some possibly predisposing dimension of personality. Indeed, in healthy male volunteers (n = 11) the behavioral and cardiovascular sensitivity to physostigmine correlated significantly with "irritability" and "emotional lability" as well as with habitually passive strategies in stress coping. The rise in plasma cortisol and norepinephrine correlated with "retardation"; that of epinephrine with active coping. Thus, the cholinergic supersensitivity in affective psychoses might be linked to a personality dimension like stress sensitivity rather than to the diagnostic category itself. Images Fig. 2 PMID:7865500

Differential inhibition of [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding to muscarinic receptors in rat brain membranes with acetylcholinesterase inhibitors.

PubMed

Lockhart, B; Closier, M; Howard, K; Steward, C; Lestage, P

2001-04-01

The potential interaction of acetylcholinesterase inhibitors with cholinergic receptors may play a significant role in the therapeutic and/or side-effects associated with this class of compound. In the present study, the capacity of acetylcholinesterase inhibitors to interact with muscarinic receptors was assessed by their ability to displace both [3H]-oxotremorine-M and [3H]-quinuclinidyl benzilate binding in rat brain membranes. The [3H]-quinuclinidyl benzilate/[3H]-oxotremorine-M affinity ratios permitted predictions to be made of either the antagonist or agonist properties of the different compounds. A series of compounds, representative of the principal classes of acetylcholinesterase inhibitors, displaced [3H]-oxotremorine-M binding with high-to-moderate potency (ambenonium>neostigmine=pyridostigmine=tacrine>physostigmine> edrophonium=galanthamine>desoxypeganine) whereas only ambenonium and tacrine displaced [3H]-quinuclinidyl benzilate binding. Inhibitors such as desoxypeganine, parathion and gramine demonstrated negligible inhibition of the binding of both radioligands. Scatchard plots constructed from the inhibition of [3H]-oxotremorine-M binding in the absence and presence of different inhibitors showed an unaltered Bmax and a reduced affinity constant, indicative of potential competitive or allosteric mechanisms. The capacity of acetylcholinesterase inhibitors, with the exception of tacrine and ambenonium, to displace bound [3H]-oxotremorine-M in preference to [3H]quinuclinidyl benzilate predicts that the former compounds could act as potential agonists at muscarinic receptors. Moreover, the rank order for potency in inhibiting acetylcholinesterase (ambenonium>neostigmine=physostigmine =tacrine>pyridostigmine=edrophonium=galanthamine >desoxypeganine>parathion>gramine) indicated that the most effective inhibitors of acetylcholinesterase also displaced [3H]-oxotremorine-M to the greatest extent. The capacity of these inhibitors to displace [3H]-oxotremorine-M binding preclude their utilisation for the prevention of acetylcholine catabolism in rat brain membranes, the latter being required to estimate the binding of acetylcholine to [3H]-oxotremorine-M-labelled muscarinic receptors. However, fasciculin-2, a potent peptide inhibitor of acetylcholinesterase (IC50 24 nM), did prevent catabolism of acetylcholine in rat brain membranes with an atypical inhibition isotherm of [3H]-oxotremorine-M binding, thus permitting an estimation of the "global affinity" of acetylcholine (Ki 85 nM) for [3H]-oxotremorine-M-labelled muscarinic receptors in rat brain.

TLC-bioautographic evaluation of in vitro anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil.

PubMed

Misra, Biswapriya B; Dey, Satyahari

2013-02-01

Sandalwood oil, rich in sesquiterpenoid alcohols, has been used in traditional medicinal systems as a relaxant and coolant. Besides, sandalwood oil is used as an ingredient in numerous skin fairness enhancing cosmetics. However, there is no available information on biological activities that relate to the above applications. Hence, the anti-tyrosinase and anti-cholinesterase potentials of sandalwood oil were probed by both TLC-bioautographic and colorimetric methods. Results obtained from colorimetric assays indicated that sandalwood oil is a potent inhibitor of tyrosinase (IC50 = 171 microg mL(-1)) and cholinesterases (IC50 = 4.8-58 microg mL(-1)), in comparison with the positive controls used in the assays, kojic acid and physostigmine, respectively. The TLC-bioautographic assays indicated that alpha-santalol, the major constituent of the oil, is a strong inhibitor of both tyrosinase and cholinesterase. These in vitro results indicate that there is a great potential of this essential oil for use in the treatment of Alzheimer's disease, as well as in skin-care.

Acetylcholine suppresses shoot formation and callusing in leaf explants of in vitro raised seedlings of tomato, Lycopersicon esculentum Miller var. Pusa Ruby.

PubMed

Bamel, Kiran; Gupta, Rajendra; Gupta, Shirish C

2016-06-02

We present experimental evidence to show that acetylcholine (ACh) causes decrease in shoot formation in leaf explants of tomato (Lycopersicon esculentum Miller var Pusa Ruby) when cultured on shoot regeneration medium. The optimum response was obtained at 10(-4) M ACh-enriched medium. ACh also causes decrease in percentage of cultures forming callus and reduces the callus mass. Inhibitors of enzymatic hydrolysis of ACh, neostigmine and physostigmine, also suppresses callogenesis and caulogenesis. On the other hand, the breakdown products of Ach, choline and acetate, do not alter the morphogenic response induced on the shoot regeneration medium. Neostigmine showed optimal reduction in shoot formation at 10(-5) M. The explants cultured on neostigmine augmented medium showed decline in the activity of ACh hydrolyzing enzyme acetylcholinesterase. ACh and neostigmine added together showed marked reduction in callus mass. These results strongly support the role of ACh as a natural regulator of morphogenesis in tomato plants.

Acetylcholine suppresses shoot formation and callusing in leaf explants of in vitro raised seedlings of tomato, Lycopersicon esculentum Miller var. Pusa Ruby

PubMed Central

Bamel, Kiran; Gupta, Rajendra; Gupta, Shirish C.

2016-01-01

ABSTRACT We present experimental evidence to show that acetylcholine (ACh) causes decrease in shoot formation in leaf explants of tomato (Lycopersicon esculentum Miller var Pusa Ruby) when cultured on shoot regeneration medium. The optimum response was obtained at 10−4 M ACh-enriched medium. ACh also causes decrease in percentage of cultures forming callus and reduces the callus mass. Inhibitors of enzymatic hydrolysis of ACh, neostigmine and physostigmine, also suppresses callogenesis and caulogenesis. On the other hand, the breakdown products of Ach, choline and acetate, do not alter the morphogenic response induced on the shoot regeneration medium. Neostigmine showed optimal reduction in shoot formation at 10−5 M. The explants cultured on neostigmine augmented medium showed decline in the activity of ACh hydrolyzing enzyme acetylcholinesterase. ACh and neostigmine added together showed marked reduction in callus mass. These results strongly support the role of ACh as a natural regulator of morphogenesis in tomato plants. PMID:27348536

Effects of carbamates on whole blood cholinesterase activity: chemical protection against soman.

PubMed

Heyl, W C; Harris, L W; Stitcher, D L

1980-01-01

The toxicity (LD50) of several carbamates, all reversible inhibitors of cholinesterase (ChE), were determined in male rabbits. These include isopropyl methylphenyl carbamate (IMPC), pyridostigmine, neostigmine, benzpyrinium and physostigmine. When 1/9 of the LD50 of the above carbamates was individually combined with atropine (A) and benactyzine (B), mecamylamine (M) or chloropromazine (CPZ) and administered to rabbits in a pretreatment regimen, most animals could be protected from a 10 LD50 challenge of Soman. If CPZ, M or B was omitted from this regimen, no rabbits survived this challenge of Soman. The protection afforded against Soman was found to be related to reversible inhibition of ChE by the carbamates; reversible ChE inhibition varied with the route of injection and with the physical properties of the carbamate. Oral administration of pyridostigmine, a quaternary carbamate, provided protection for 24 hours. When the pretreatment included four components (pyridostigmine, A, M and B), the LD50 of Soman was raised 30.8 times in rabbits.

Reflex reticular myoclonus: relationship to some brainstem pathophysiological mechanisms.

PubMed

Rektor, I; Kadanka, Z; Bednarik, J

1991-04-01

Two patients with reflex reticular myoclonus [RRM] were tested electrophysiologically and pharmacologically. In one of the cases the underlying disease was chronic Lyme borreliosis. In the other, the RRM attacks may have been associated with procarbazine therapy applied for Hodgkin's disease. No cortical lesion could be demonstrated either clinically or electrophysiologically [EEG, averaged EEg preceeding the jerks, SSEP]. An EMG analysis of the jerks revealed the shortest latency in the muscles innervated by the accessory nerve. The latencies became longer in a more rostral muscle [masseter], as well as in a more caudal one, the muscles innervated by the facial nerve were spared. it is presumed that the complete movement pattern of the myoclonus residues in the jerk generating structure. RRM in the described cases differs from the startle by sparing the facial nerve and from the Papio papio baboon non-epileptic myoclonus by the activating effect of physostigmine. A partial therapeutic effect was achieved with a serotonine precursor, but a GABAergic therapy proved to be the most effective.

Diagnosing and treating Phthirus pubis palpebrarum.

PubMed

Couch, J M; Green, W R; Hirst, L W; de la Cruz, Z C

1982-01-01

Phthiriasis palpebrarum is an uncommon cause of blepharitis and conjunctivitis and may easily be overlooked. A high index of suspicion and careful examination of the patient's lid margins and eyelashes will lead to the proper diagnosis. Treatment is best accomplished by careful removal of the lice and nits (louse eggs) from the patient's lashes. Local application of a pediculocide such as yellow mercuric oxide N.F. 1% ophthalmic ointment applied twice daily for one week or 0.25% physostigmine (Eserine) ointment applied twice daily for a minimum of ten days, to the lid margins should be considered when the total removal of Phthirus pubis and nits is not possible mechanically. Body hair should be examined for infestation with lice and treated with gamma benzene hexachloride shampoo. This medication should be used with caution in infants, children and pregnant women. Family members, sexual contacts, and close companions should be examined and treated appropriately; clothing, linen and personal items should be disinfected with heat of 50 degrees C for 30 minutes.

The sympathetic mechanism in the isolated pulmonary artery of the rabbit

PubMed Central

Bevan, J. A.; Su, C.

1964-01-01

The nature of postganglionic sympathetic nervous transmission to vascular muscle in vitro was studied using the recurrent cardiac nerve-pulmonary artery preparation of the rabbit. Experiments, similar to those which in other tissues have provided evidence to support a role for acetylcholine at the sympathetic postganglionic nerve-effector cell junction, were carried out. The contractile response of the isolated artery to acetylcholine was blocked completely by atropine. High concentrations of acetylcholine and of hemicholinium had no effect on the contractile response to sympathetic nerve stimulation. Physostigmine, atropine and hemicholinium were without influence on the relationship between nerve stimulus frequency and response. Yohimbine, bretylium and reserpine blocked completely the response to nerve stimulation but did not affect that to applied acetylcholine. These results support the view that transmission in this preparation at the sympathetic postganglionic nerve-effector cell junction is mediated by an adrenaline-like transmitter and provide no evidence for the view that acetylcholne is involved at this site. PMID:14126048

Effect of intravenously-administered putative and potential antagonists of ethanol on sleep time in ethanol-narcotized mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hatch, R.C.; Jernigan, A.D.

Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly by a large dose of dl-amphetamine and by 4-aminopyridine. Significant increases were also produced by small and large doses of aminophylline and by yohimbine. MST was not altered significantly by small and medium doses of dl-amphetamine, a medium dose ofmore » aminophylline, or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST. 36 references, 1 table.« less

Neutral endopeptidase inhibitors potentiate substance P-induced contraction in gut smooth muscle.

PubMed

Djokic, T D; Sekizawa, K; Borson, D B; Nadel, J A

1989-01-01

To determine the role of endogenous neutral endopeptidase (NEP), also called enkephalinase (EC 3.4.24.11), in regulating tachykinin-induced contraction of gut smooth muscle, we studied the effects of NEP inhibitors on the contractile responses to substance P (SP) in isolated longitudinal strips of ileum or duodenum in rats and ferrets. Leucine-thiorphan and phosphoramidon shifted the concentration-response curves of SP to lower concentrations in all tissues studied, but the sensitivity to SP was greater and the effect of leucine-thiorphan was less in the ferret, a finding that correlated with the observation that the ferret ileum contained substantially less NEP activity than rat ileum. Captopril, bestatin, MGTA, leupeptin, and physostigmine did not alter contractile responses to SP, suggesting that kininase II, aminopeptidases, carboxypeptidase N, serine proteinases, and acetylcholinesterase do not modulate the SP-induced effects. These studies suggest that, in the ileum and duodenum, NEP modulates the actions of SP and, furthermore, that the sensitivity of tissues may be determined, at least in part, by the amount of enzymatically active NEP present.

Rat isolated phrenic nerve-diaphragm preparation for pharmacological study of muscle spindle afferent activity: effect of oxotremorine.

PubMed Central

Ganguly, D K; Nath, D N; Ross, H G; Vedasiromoni, J R

1978-01-01

1. Muscle spindle afferent discharges exhibiting an approximately linear length-frequency relation could be recorded from the phrenic nerve in the isolated phrenic nerve-diaphragm preparation of the rat. 2. Muscle spindle afferent discharges could be identified by their characteristic "spindle pause" during muscle contraction and by their response to succinylcholine. 3. Cholinergic influence on spontaneous and stretch-induced afferent discharges was indicated by the augmentation produced by physostigmine and acetylcholine. (+)-Tubocurarine, but not atropine, prevented this augmentation indicating the presence of curariform cholinoceptors in muscle spindles. 4. Acetylcholine did not appear to be involved in the genesis of spindle afferent discharges as incubation with hemicholinium-3 and (+)-tubocurarine failed to affect the rate of spontaneous and stretch-induced spindle discharges. 5. Oxotremorine markedly increased the rate of spontaneous and stretch-induced spindle afferent discharges and this effect was prevented in the presence of hemicholinium-3 and (+)-tubocurarine. 6. These results with oxotremorine are of interest in connection with the observation that muscle spindle afferents and hyperactive in Parkinsonian patients. PMID:151569

Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs

NASA Technical Reports Server (NTRS)

Kandasamy, S. B.; Williaes, B. A.

1983-01-01

It is shown that the intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP) induced hyperthermia in guinea pigs which was not mediated through prostaglandins or norepinephrine since a prostaglandin synthesis inhibitor and an alpha-adrenergic receptor blocking agent did not antagonize the hyperthermia. However, the hyperthermic response to Db-cAMP was attenuated by the central administration of a beta-adrenergic receptor antagonist, which indicates that cAMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production and conservation. The central administration of Db-cGMP produced hypothermia which was not mediated via histamine H1 or H2 receptors and serotonin. The antagonism of hypothermia induced by Db-cGMP and acetylcholine + physostigmine by central administration of a cholinergic muscarine receptor antagonist and not by a cholinergic nicotinic receptor antagonist suggests that cholinoceptive neurons and endogenous cGMP may regulate heat loss through cholinergic muscarine receptors. It is concluded that these results indicate a regulatory role in thermoregulation provided by a balance between opposing actions of cAMP and cGMP in guinea pigs.

Variable effects of soman on macromolecular secretion by ferret trachea

DOE Office of Scientific and Technical Information (OSTI.GOV)

McBride, R.K.; Zwierzynski, D.J.; Stone, K.K.

1991-01-01

The purpose of this study was to examine the effect of the anticholinesterase agent, soman, on macromolecular secretion by ferret trachea, in vitro. We mounted pieces of ferret trachea in Ussing-type chambers. Secreted sulfated macromolecules were radiolabeled by adding 500 microCi of {sup 35}SO{sub 4} to the submucosal medium and incubating for 17 hr. Soman added to the submucosal side produced a concentration-dependent increase in radiolabeled macromolecular release with a maximal secretory response (mean +/- SD) of 202 +/- 125% (n = 8) relative to the basal secretion rate at a concentration of 10{sup {minus} 7} M. The addition ofmore » either 10{sup {minus}6} M pralidoxime (acetylcholinesterase reactivator) or 10{sup {minus}6} M atropine blocked the response to 10{sup {minus}7} M soman. At soman concentrations greater than 10{sup {minus}7} M, secretion rate decreased and was not significantly different from basal secretion. Additional experiments utilizing acetylcholine and the acetylcholinesterase inhibitor, physostigmine, suggest that inhibition of secretion by high concentrations of soman may be due to a secondary antagonistic effect of soman on muscarinic receptors.« less

Interactions between acetylcholine, 5-hydroxytryptamine, nicotine and morphine on isolated rabbit atria

PubMed Central

Chittal, S. M.; Dadkar, N. K.; Gaitondé, B. B.

1968-01-01

1. The effects of 5-hydroxytryptamine (5-HT) and morphine on the responses to acetylcholine and nicotine of isolated rabbit atria were studied. 2. 5-Hydroxytryptamine (10 μg/ml.) and morphine (20 μg/ml.) blocked the negative chronotropic and inotropic actions of acetylcholine. 3. Nicotine (20 μg/ml.) produced stimulation of the atria, which was blocked by dichlorisoprenaline, morphine, 5-HT, bretylium and hemicholinium. Hemicholinium block was reversed by choline. 4. In reserpinized preparations, nicotine produced inhibition of atria and this action was also blocked by atropine, 5-HT and morphine. Inhibition induced by nicotine was potentiated by physostigmine. 5. 5-Hydroxytryptamine (20 μg/ml.) produced stimulation of atria. This was blocked by bretylium and reduced by hemicholinium. Hemicholinium block was reversed by choline. 6. It is concluded that 5-HT in low concentrations acts as a weak agonist at the cholinoceptive receptors and therefore blocks the action of acetylcholine. Furthermore, nicotine and larger doses of 5-HT have actions on ganglionic structures and liberate acetylcholine, which in turn releases catecholamines. PMID:4386371

In vitro acetylcholinesterase activity of peptide derivatives isolated from two species of Leguminosae.

PubMed

Alves, Clayton Q; Lima, Luciano S; David, Jorge M; Lima, Marcos V B; David, Juceni P; Lima, Fernanda W M; Pedroza, Kelly C M C; Queiroz, Luciano P

2013-07-01

Cratylia mollis Martius ex Benth. and Cenostigma macrophyllum Tul. (Leguminosae) are both endemic Brazilian plants and they are used by the natives as medicinal plants, and the leaves of C. mollis are also employed as forage for cattle during the dry season of region. Isolation of the compounds responsible for the acetylcholinesterase (AChE) inhibition from the CHCl3 active extract. Two peptidic compounds were isolated by chromatographic techniques from the CHCl3 extract of the leaves of C. mollis and C. macrophyllum. They were identified by spectrometric data analysis (MS and NMR) and they were subjected to AChE inhibition employing Ellman's test. The peptides were identified as N-benzoylphenylalaninoyl-phenlyalaninolacetate (aurentiamide acetate) (1) and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2). Both peptides 1 and 2 exhibit AChE inhibition, with IC50 values equal to 111.34 µM and 137.6 µM, respectively. Compound 1 (aurentiamide acetate) has rarely been isolated from the Leguminosae family, and N-benzoylphenylalaninyl-N-benzoylphenylalaninate (2) is a compound that has never previously been isolated from this family. Compound 1 is shown to be a potent inhibitor of AChE, with IC50 values similar to the physostigmine control (141.51 µM).

Flavonoid Composition and Biological Activities of Ethanol Extracts of Caryocar coriaceum Wittm., a Native Plant from Caatinga Biome.

PubMed

Alves, Daniela Ribeiro; Maia de Morais, Selene; Tomiotto-Pellissier, Fernanda; Miranda-Sapla, Milena Menegazzo; Vasconcelos, Fábio Roger; da Silva, Isaac Neto Goes; Araujo de Sousa, Halisson; Assolini, João Paulo; Conchon-Costa, Ivete; Pavanelli, Wander Rogério; Freire, Francisco das Chagas Oliveira

2017-01-01

Caryocar coriaceum fruits, found in Brazilian Cerrado and Caatinga, are commonly used as food and in folk medicine, as anti-inflammatory, bactericide, fungicide, leishmanicide, and nematicide. Due to the biological potential of this plant, this study focuses on the evaluation of antifungal and antileishmanial activities, including anticholinesterase and antioxidant tests, correlating with total phenols and flavonoids content. Peel extracts contain higher yield of phenols and flavonoids as analyzed by spectrophotometric methods. HPLC analysis of flavonoids revealed that isoquercitrin is the main flavonoid in both parts of the fruit, and peel extract showed the best antioxidant activity. In the inhibition of the acetylcholinesterase assay, both extracts demonstrate action comparable to physostigmine. The antimicrobial activity of extracts was evaluated against strains of Malassezia sp. and Microsporum canis , using the broth microdilution technique, in which the extracts showed similar MIC and MFC. The extracts present antileishmanial activity and low toxicity on murine macrophages and erythrocytes. Therefore, these results suggest a potential for the application of C. coriaceum fruit's ethanol extracts in the treatment against dermatophyte fungi and leishmaniasis, probably due to the presence of active flavonoids. Further in vivo studies are recommended aiming at the development of possible new pharmaceutical compounds.

Flavonoid Composition and Biological Activities of Ethanol Extracts of Caryocar coriaceum Wittm., a Native Plant from Caatinga Biome

PubMed Central

Alves, Daniela Ribeiro; Tomiotto-Pellissier, Fernanda; da Silva, Isaac Neto Goes; Araujo de Sousa, Halisson; Assolini, João Paulo; Freire, Francisco das Chagas Oliveira

2017-01-01

Caryocar coriaceum fruits, found in Brazilian Cerrado and Caatinga, are commonly used as food and in folk medicine, as anti-inflammatory, bactericide, fungicide, leishmanicide, and nematicide. Due to the biological potential of this plant, this study focuses on the evaluation of antifungal and antileishmanial activities, including anticholinesterase and antioxidant tests, correlating with total phenols and flavonoids content. Peel extracts contain higher yield of phenols and flavonoids as analyzed by spectrophotometric methods. HPLC analysis of flavonoids revealed that isoquercitrin is the main flavonoid in both parts of the fruit, and peel extract showed the best antioxidant activity. In the inhibition of the acetylcholinesterase assay, both extracts demonstrate action comparable to physostigmine. The antimicrobial activity of extracts was evaluated against strains of Malassezia sp. and Microsporum canis, using the broth microdilution technique, in which the extracts showed similar MIC and MFC. The extracts present antileishmanial activity and low toxicity on murine macrophages and erythrocytes. Therefore, these results suggest a potential for the application of C. coriaceum fruit's ethanol extracts in the treatment against dermatophyte fungi and leishmaniasis, probably due to the presence of active flavonoids. Further in vivo studies are recommended aiming at the development of possible new pharmaceutical compounds. PMID:29081821

Recovery of diminished mealtime-associated anticipatory behavior by aniracetam in aged rats.

PubMed

Tanaka, Y; Kurasawa, M; Nakamura, K

2000-08-01

Disease- or age-related neuropsychiatric symptoms and cognitive and chronobiological impairments greatly aggravate the activities of daily living (ADL) in patients. The present study evaluates the effects of aniracetam on a decline in mealtime-associated anticipatory behavior in aged rats, as an animal model of temporally regulated behaviors or habitual daily activities. Aged rats showed a lower but typical nocturnal motor activity rhythm than young rats when the animals were fed ad lib. Mealtime-associated anticipatory behavior emerged in young rats when the rats were fed at a fixed time for 6 days, but the activity in aged rats was diminished. Repeated administration of aniracetam (100 mg/kg PO) or physostigmine (0.1 mg/kg SC) for 7 days ameliorated the impaired anticipatory behavior in aged rats. Nefiracetam (10 mg/kg PO) was ineffective. All compounds tested had no effect on appetite or motor ability. These results indicate that aging disturbs the timing or temporal regulation of anticipatory behavior, probably resulting from dysfunction in a food-entrainable oscillator linked to central cholinergic systems. The restoration of the time-keeping ability by aniracetam may be mediated by the facilitation of reticulothalamic cholinergic neurotransmission, and the action may lead to the improvement of declined ADL in stroke patients.

Protection against both lethal and behavioral effects of soman.

PubMed

Harris, L W; McDonough, J H; Stitcher, D L; Lennox, W J

1984-01-01

This work developed two drug mixtures which alone had no effect on performance of a criterion behavior but when given as a pretreatment would protect against organophosphate-induced lethality and incapacitation. Candidate drugs (alone and together) were given to rats trained to respond on a two-component Fixed Ratio 10 - Extinction (FR10-EXT) schedule. After generating dose response curves for each cholinolytic drug, mixtures of atropine (A) + mecamylamine (M) + pyridostigmine (Py) or physostigmine (Ph) were prepared and a combination of doses that produced no effects on operant performance was determined (Mix I:A = .78, M = .78, Py = .056 mg/kg; Mix II:A = .78, M = .78, Ph = .026 mg/kg). Both pretreatment mixtures provided equivalent protection against the lethal effects of the organophosphate soman; however only Mix II was capable of reversing soman-induced physical incapacitation (PI) as assessed by performance on an accelerating rotarod or FR10 responding. Pretreatment of animals with Mix II resulted in significantly higher levels of brain acetylcholinesterase (AChE) than Mix I pretreated subjects 4 hrs after 1.3 LD50 soman, although peripheral AChE levels were not different. The results indicate organophosphate-induced PI can be attenuated by pretreatment with tertiary carbamates which protect significant amounts of brain AChE from irreversible inhibition.

Effects of inhibitors of acetylcholine synthesis on brain acetylcholine and survival in soman-intoxicated animals.

PubMed

Harris, L W; Stitcher, D L; Hey, W C

1982-05-31

The effects of hemicholinium-3 (HC-3) or 4-(l-naphthylvinyl)pyridine (4-NVP) alone and together with cholinolytics and/or cholinesterase inhibitors on brain acetylcholine (ACh) levels and survival were studied. Intracerebroventricular (ICVT) injection of 10 micrograms HC-3 280 min before euthanasia by microwave irradiation reduced rat cerebral ACh levels from 28.4 to 5.4 nmoles ACh/g wet tissue. In rats pretreated with HC-3 alone or with other pretreatment drugs prior to giving up to 2.7 LD50 of soman, iv, cerebral ACh levels increased very little, but in animals not receiving HC-3, brain ACh levels increased to 67.1 nmoles. Treatment of unpoisoned rats with 4-NVP resulted in a significant (26%) reduction in ACh. The inclusion of atropine with 4-NVP caused sign-free doses of physostigmine to produce toxic signs in rabbits and did not enhance the efficacy of carbamate pretreatment against soman. Pretreatment of rabbits with pyridostigmine and atropine methyl nitrate (AMN) failed to provide any protection against soman, but when HC-3, ICVT, was included with those drugs, the protective ratio (PR), against soman was increased excess ACh is a primary lesion in organophosphorus anticholinesterase intoxication and that the central nervous system is quite sensitive to excesses of ACh.

Nature as a source of metabolites with cholinesterase-inhibitory activity: an approach to Alzheimer's disease treatment.

PubMed

Pinho, Brígida R; Ferreres, Federico; Valentão, Patrícia; Andrade, Paula B

2013-12-01

Alzheimer's disease (AD) is the most common cause of dementia, being responsible for high healthcare costs and familial hardships. Despite the efforts of researchers, no treatment able to delay or stop AD progress exists. Currently, the available treatments are only symptomatic, cholinesterase inhibitors being the most widely used drugs. Here we describe several natural compounds with anticholinesterase (acetylcholinesterase and butyrylcholinesterase) activity and also some synthetic compounds whose structures are based on those of natural compounds. Galantamine and rivastigmine are two cholinesterase inhibitors used in therapeutics: galantamine is a natural alkaloid that was extracted for the first time from Galanthus nivalis L., while rivastigmine is a synthetic alkaloid, the structure of which is modelled on that of natural physostigmine. Alkaloids include a high number of compounds with anticholinesterases activity at the submicromolar range. Quinones and stilbenes are less well studied regarding cholinesterase inhibition, although some of them, such as sargaquinoic acid or (+)-α-viniferin, show promising activity. Among flavonoids, flavones and isoflavones are the most potent compounds. Xanthones and monoterpenes are generally weak cholinesterase inhibitors. Nature is an almost endless source of bioactive compounds. Several natural compounds have anticholinesterase activity and others can be used as leader compounds for the synthesis of new drugs. © 2013 Royal Pharmaceutical Society.

Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease.

PubMed Central

Wright, C I; Guela, C; Mesulam, M M

1993-01-01

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase and butyrylcholinesterase activity in Alzheimer disease. We previously reported that traditional acetylcholinesterase inhibitors such as BW284C51, tacrine, and physostigmine were more potent inhibitors of the acetylcholinesterase in normal axons and cell bodies than of the acetylcholinesterase in plaques and tangles. We now report that the reverse pattern is seen with indoleamines (such as serotonin and its precursor 5-hydroxytryptophan), carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal axons and cell bodies. This shift in enzymatic affinity may lead to the abnormal protein processing that is thought to play a major role in the pathogenesis of Alzheimer disease. The availability of pharmacological and dietary means for altering brain indoleamines raises therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer disease. Images PMID:8421706

Continuous flow immobilized enzyme reactor-tandem mass spectrometry for screening of AChE inhibitors in complex mixtures.

PubMed

Forsberg, Erica M; Green, James R A; Brennan, John D

2011-07-01

A method is described for identifying bioactive compounds in complex mixtures based on the use of capillary-scale monolithic enzyme-reactor columns for rapid screening of enzyme activity. A two-channel nanoLC system was used to continuously infuse substrate coupled with automated injections of substrate/small molecule mixtures, optionally containing the chromogenic Ellman reagent, through sol-gel derived acetylcholinesterase (AChE) doped monolithic columns. This is the first report of AChE encapsulated in monolithic silica for use as an immobilized enzyme reactor (IMER), and the first use of such IMERs for mixture screening. AChE IMER columns were optimized to allow rapid functional screening of compound mixtures based on changes in the product absorbance or the ratio of mass spectrometric peaks for product and substrate ions in the eluent. The assay had robust performance and produced a Z' factor of 0.77 in the presence of 2% (v/v) DMSO. A series of 52 mixtures consisting of 1040 compounds from the Canadian Compound Collection of bioactives was screened and two known inhibitors, physostigmine and 9-aminoacridine, were identified from active mixtures by manual deconvolution. The activity of the compounds was confirmed using the enzyme reactor format, which allowed determination of both IC(50) and K(I) values. Screening results were found to correlate well with a recently published fluorescence-based microarray screening assay for AChE inhibitors.

Deanol acetamidobenzoate (Deaner) in tardive dyskinesia.

PubMed

Stafford, J R; Fann, W E

1977-12-01

A total of twenty-nine patients have thus far been treated with deanol in various dosage levels for periods ranging from five to thirty days. Clinical response has been pronounced, even dramatic, in seven patients, moderate but significant in nine patients, and slight to insignificant in thirteen others. Videotape rating and quantitative accelerometry, to the extent that they constitute novel and stress-inducing experiences may not be representative of global clinical changes. Deanol did not produce the anticipated elevation in choline levels postulated to be one mechanism of its action. The failure of deanol to achieve this effect may most probably be attributed to interval after last dose, to inadequate level of deanol or to some alteration in choline metabolism in the presence of deanol. The etiology of tardive dyskinesia at biochemical and structural levels is complex. For some patients improvement has been dramatic and clearly associated with deanol. Others appear to exhibit minimal response which cannot be differentiated from placebo or environmental effects. Our present strategy, in common with that of other authors includes the administration of a "challenge" dose of rapid acting injectable cholinomimetic agents (e.g. physostigmine) and dopamine-blocking agents (e.g. haloperidol) with placebo controls. In this manner therapy may be more rationally selected for long-term use and may logically include deanol. The correlation of such predictive challenges with response to long-term treatment is an area for much more well controlled study.

Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer's disease.

PubMed

Konrath, Eduardo Luis; Passos, Carolina dos Santos; Klein, Luiz Carlos; Henriques, Amélia T

2013-12-01

The inhibition of acetylcholinesterase (AChE), the key enzyme in the breakdown of acetylcholine, is currently the main pharmacological strategy available for Alzheimer's disease (AD). In this sense, many alkaloids isolated from natural sources, such as physostigmine, have been long recognized as acetyl- and butyrylcholinesterase (BChE) inhibitors. Since the approval of galantamine for the treatment of AD patients, the search for new anticholinesterase alkaloids has escalated, leading to promising candidates such as huperzine A. This review aims to summarize recent advances in current knowledge on alkaloids as AChE and BChE inhibitors, highlighting structure-activity relationship (SAR) and docking studies. Natural alkaloids belonging to the steroidal/triterpenoidal, quinolizidine, isoquinoline and indole classes, mainly distributed within Buxaceae, Amaryllidaceae and Lycopodiaceae, are considered important sources of alkaloids with anti-enzymatic properties. Investigations into the possible SARs for some active compounds are based on molecular modelling studies, predicting the mode of interaction of the molecules with amino acid residues in the active site of the enzymes. Following this view, an increasing interest in achieving more potent and effective analogues makes alkaloids good chemical templates for the development of new cholinesterase inhibitors. The anticholinesterase activity of alkaloids, together with their structural diversity and physicochemical properties, makes them good candidate agents for the treatment of AD. © 2013 Royal Pharmaceutical Society.

Cholinesterase enzymes inhibitors from the leaves of Rauvolfia reflexa and their molecular docking study.

PubMed

Fadaeinasab, Mehran; Hadi, A Hamid A; Kia, Yalda; Basiri, Alireza; Murugaiyah, Vikneswaran

2013-03-25

Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

Acute Datura Stramonium poisoning in East of Iran - a case series.

PubMed

Amini, Mahnaz; Khosrojerdi, Hamid; Afshari, Reza

2012-01-01

Datura Stramonium (DS) is a common weed along roadsides, in cornfields and pastures and in waste areas. It belongs to the family Solanaceae and its toxic components are tropane belladonna alkaloids. It has been used voluntarily by teenagers for its hallucinogenic effect. The plant is named in Iran as Tatoore. Symptoms and signs of acute D. Stramonium poisoning usually are similar to anticholinergic syndrome. This study is done in order to clarify the status of this poisoning in our region. This study is a case series on all patients admitted to Imam Reza Hospital, Mashhad, Iran, with acute D. Stramonium poisoning between 2008 and 2011. We observed their symptoms, signs, routine laboratory test results and treatment used to control their symptoms. There were 19 patients included in our study. Children were poisoned more commonly than teenagers and poisoning in adults was rare. All of the children ingested the plant accidentally. The most presenting symptom was irritability and the most common sign was sinus tachycardia. There was not any presentation of seizure or coma. Most of the symptoms were controlled by parenteral benzodiazepines and there were no need to use of cholinergic agents such as physostigmine. Our study showed most of D. Stramonium poisoned population in our region are children. We suggest decreasing accessibility to the plant in order to decrease the incidence of its poisoning.

Solanaceae III: henbane, hags and Hawley Harvey Crippen.

PubMed

Lee, M R

2006-12-01

Hyoscyamus, the henbane, is one of the drugs of the ancients. Initially used both as a poison and narcotic, it was widely adopted by witches, wizards and soothsayers as a component of their hallucinatory and flying ointments. It was also used by notorious poisoners such as Madame Voisin in France. Eventually, in the nineteenth century its active principle was isolated by Ladenburg and called l-hyoscine. It proved to be a tropane alkaloid very similar to atropine. These two alkaloids proved to be very important in the study of the parasympathetic component of the autonomic nervous system, and together with physostigmine, allowed the major neurotransmitter acetylcholine to be isolated and its mechanisms of action to be characterised. The Crippen murder case in 1910 gave hyoscine further fame, indeed, notoriety. The unassuming homeopathic doctor murdered his wife with the alkaloid and then decamped for Canada with his mistress Ethel Le Neve. The case became a worldwide sensation for several reasons: the arrest of the fugitive couple by wireless telegraphy (Marconigram) and the extensive chemical and histological evidence presented by Willcox and Spilsbury. Some authorities claim that this was the beginning of the science of forensic medicine in Britain. Hyoscine is now hardly ever used in modern therapeutics but its history from antiquity to the witches and on to Dr Crippen is both bizarre and fascinating.

Cholinergic enhancement of visual attention and neural oscillations in the human brain.

PubMed

Bauer, Markus; Kluge, Christian; Bach, Dominik; Bradbury, David; Heinze, Hans Jochen; Dolan, Raymond J; Driver, Jon

2012-03-06

Cognitive processes such as visual perception and selective attention induce specific patterns of brain oscillations. The neurochemical bases of these spectral changes in neural activity are largely unknown, but neuromodulators are thought to regulate processing. The cholinergic system is linked to attentional function in vivo, whereas separate in vitro studies show that cholinergic agonists induce high-frequency oscillations in slice preparations. This has led to theoretical proposals that cholinergic enhancement of visual attention might operate via gamma oscillations in visual cortex, although low-frequency alpha/beta modulation may also play a key role. Here we used MEG to record cortical oscillations in the context of administration of a cholinergic agonist (physostigmine) during a spatial visual attention task in humans. This cholinergic agonist enhanced spatial attention effects on low-frequency alpha/beta oscillations in visual cortex, an effect correlating with a drug-induced speeding of performance. By contrast, the cholinergic agonist did not alter high-frequency gamma oscillations in visual cortex. Thus, our findings show that cholinergic neuromodulation enhances attentional selection via an impact on oscillatory synchrony in visual cortex, for low rather than high frequencies. We discuss this dissociation between high- and low-frequency oscillations in relation to proposals that lower-frequency oscillations are generated by feedback pathways within visual cortex. Copyright © 2012 Elsevier Ltd. All rights reserved.

Pharmacological specificity of N-methyl-D-aspartate discrimination in rats.

PubMed

Grech, D M; Willetts, J; Balster, R L

1993-04-01

The purpose of this study was to provide further information on the usefulness of N-methyl-D-aspartate (NMDA) discrimination in rats as a behavioral model for NMDA receptor activation. The pharmacological specificity of the NMDA discriminative stimulus was examined in rats trained to discriminate 30 mg/kg, i.p. NMDA from saline using a 2-lever fixed-ratio (FR) 32 food reinforcement schedule. Pharmacologically diverse centrally-acting agents were examined for their ability to substitute for NMDA. Morphine did not substitute for NMDA; neither did the central stimulants, caffeine and (+)-amphetamine, which produced a maximum mean of only 16 and 35% NMDA-lever responding, respectively. Pentylenetetrazol and picrotoxin also did not substitute for NMDA. Compounds interacting with cholinergic neurotransmission including nicotine, physostigmine, arecoline and mecamylamine, produced at best, only intermediate levels of NMDA-lever responding (32-61%), with the highest levels of NMDA-lever responding generally occurring at doses that also reduced rates of responding. These results suggest that the discriminative stimulus properties of NMDA are dissimilar from those of a number of centrally-acting drugs. Combined with the results of studies indicating that the NMDA discriminative stimulus can be antagonized by competitive NMDA antagonists, these results provide further evidence that NMDA receptor activation is the basis of NMDA discrimination and that this model may be useful for studying site-selective NMDA agonists and antagonists.

Piracetam and aniracetam antagonism of centrally active drug-induced antinociception.

PubMed

Galeotti, N; Ghelardini, C; Bartolini, A

1996-04-01

The effects of the nootropic drugs piracetam and aniracetam on antinociception induced by baclofen, bicuculline, and picrotoxin and on baclofen-induced muscle relaxation were studied in mice. Antinociception was investigated using both the hot plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Both behaviour inhibition and muscle relaxation were observed by using the rota-rod test. Piracetam (30 mg/kg, IP) and aniracetam (10 mg/kg, PO) reduced baclofen, bicuculline, and picrotoxin antinociception without modifying analgesia induced by non-GABAergic drugs such as morphine, physostigmine, clomipramine, and diphenhydramine. In this concentration range, piracetam, and aniracetam were also able to reduce the inhibition of rota-rod performance. At higher doses piracetam (100 mg/kg, IP) and aniracetam (100 mg/kg, PO) were able to completely prevent baclofen antinociception. However, when prevention of GABAergic antinociception was complete, piracetam and aniracetam were able to block non-GABAergic antinociception also. comparing the effects of piracetam and aniracetam with those exerted by the GABAB antagonist CGP 35348, a reduction of non-GABAergic analgesia was also observed using higher doses of CGP 35348 (2.5 micrograms per mouse ICV). The present results indicate that piracetam and aniracetam, by preventing both of the investigated effects of baclofen, have some selectivity against GABAB-mediated inhibition. The well-known activity of piracetam and aniracetam on learning and memory might, therefore, depend, at least in part, on the removal of inhibitory GABAB mechanisms that impair attention and cognitive functions.

Hydrolysis of Synthetic Esters by the Antibacterial Agent in Serum

PubMed Central

Yotis, William W.

1966-01-01

Yotis, William W. (Loyola University, Chicago, Ill.). Hydrolysis of synthetic esters by the antibacterial agent in serum. J. Bacteriol. 91:488–493. 1966.—An antistaphylococcal serum agent was assayed colorimetrically, manometrically, and titrimetrically for esterase activity. p-Nitrophenol acetate, triacetin, l-lysine methyl and ethyl ester, and norleucine methyl ester were hydrolyzed by the antistaphylococcal agent. Acetylcholine and benzoylcholine esters, triolein, tristearin, and p-tosylarginine methyl ester were not attacked by this agent. With p-nitrophenol acetate as substrate, optimal activity occurred at pH 7.4. Incubation at 60 C for 30 min reduced drastically the esterase activity of the antistaphylococcal agent, and incubation at 75 C for 30 min abolished the esterase activity of this agent. Almost complete inhibition of esterase activity was observed with 0.001 m HgCl2, ZnSO4, and ethylenediaminetetraacetic acid (EDTA). EDTA inhibition could be reversed by the addition of CaCl2, but not MgCl2. Cysteine reversed the inhibition of HgCl2. NaF, atoxyl, diisopropyl fluorophosphate, quinine, and physostigmine did not influence the esterase activity of the antibacterial agent. The demonstration of esterase activity of both the antistaphylococcal agent and coagulase may shed further light on the reported ability of coagulase to neutralize the antistaphylococcal activity of this agent, or the prevention of absorption of the agent on the staphylococcal cell surface. In addition, the colorimetric procedure described in this report may be a convenient tool in assaying the potency of the antistaphylococcal agent. Images PMID:4956776

Improved thin-layer chromatography bioautographic assay for the detection of actylcholinesterase inhibitors in plants.

PubMed

Yang, Zhong-Duo; Song, Zhu-Wen; Ren, Jin; Yang, Ming-Jun; Li, Shuo

2011-01-01

Thin-layer chromatography (TLC) bioautographic method is a simple and rapid method to screen acetylcholinesterase inhibitors from plant extracts. However, the high consumption of enzyme (6 U/mL) in current methods makes the procedure expensive, which is an obstacle to scientific research centers lacking funding. To develop a new low-cost TLC bioautographic method. A series of compounds, as substrates, were synthesised and their ability to be hydrolysed by acetylcholinesterase was evaluated by the HPLC method. 4-Methoxyphenyl acetate (14) was proved to be an appropriate substrate for TLC bioautographic assay. Therefore a new and cheap TLC bioautographic assay was set up. The mechanism of this new method is that the enzyme converts 4-methoxylphenyl acetate into 4-methoxyphenol, which reacts with a solution of potassium ferricyanide ([K₃(FeCN)₆]) and iron chloride hexahydrate (FeCl₃·6H₂O) to make an aquamarine blue coloured background on the TLC plates. Regions of the TLC plate which contain acetylcholinesterase inhibitors show up as light yellow spots against the background. The consumption of enzyme (1 U/mL) in the new method is low and the detection limit of two known acetylcholinesterase inhibitors, huperzine A (0.0001 μg) and physostigmine (0.001 μg), for this assay are close to published values. A low-cost TLC bioautographic method was developed, which will benefit research groups pursuing natural acetylcholinesterase inhibitors. Copyright © 2011 John Wiley & Sons, Ltd.

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication.

PubMed

Faria, Melissa; Prats, Eva; Padrós, Francesc; Soares, Amadeu M V M; Raldúa, Demetrio

2017-04-01

Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included "standard therapy" drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-D-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC 50 )] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.

An animal model of fetal alcohol spectrum disorder: Trace conditioning as a window to inform memory deficits and intervention tactics.

PubMed

Hunt, Pamela S; Barnet, Robert C

2015-09-01

Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5g/kg/day ethanol on postnatal days (PD) 4-9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as 'gap filling' completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibitors of neutral endopeptidase potentiate electrically and capsaicin-induced noncholinergic contraction in guinea pig bronchi.

PubMed

Djokic, T D; Nadel, J A; Dusser, D J; Sekizawa, K; Graf, P D; Borson, D B

1989-01-01

To evaluate the role of airway neutral endopeptidase (NEP) in the regulation of contraction of airway smooth muscle in response to endogenous tachykinins, we studied the effects of the NEP inhibitor phosphoramidon on contractions of guinea pig bronchial smooth muscle strips induced by either electrical field stimulation (EFS) or by capsaicin. In the presence of atropine (10(-6) M), propranolol (10(-6) M), phentolamine (10(-5) M), indomethacin (10(-6) M) and pyrilamine (5 x 10(-6) M) EFS (biphasic; pulse width, 1.0 msec; frequency 0.5-5 Hz for 30 sec; intensity, 20 V) produced noncholinergic, nonadrenergic muscle contraction in a frequency-dependent fashion (P less than .001). Phosphoramidon potentiated the contractile responses to EFS (P less than .01). Leucine-thiorphan (10(-5) M), another NEP inhibitor, potentiated EFS-induced contraction in a similar fashion as phosphoramidon (186 and 182% of control, respectively; each comparison, P less than .025). Captopril, bestatin, leupeptin and physostigmine (each drug, 10(-5) M) were without effect (P greater than .5, N = 5). Capsaicin (1.5 x 10(-8) M) produced long-lasting atropine-resistant smooth muscle contraction, an effect potentiated by phosphoramidon (10(-5) M (P less than .001). Removal of the epithelium slightly but significantly (P less than .05) increased the contractile responses to capsaicin and to EFS at impulse frequencies of 2 and 5 Hz, and phosphoramidon substantially increased contractions in tissues without epithelium. The trachea, bronchi and lungs each contained significant NEP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

An Animal Model of Fetal Alcohol Spectrum Disorder: Trace Conditioning as a Window to Inform Memory Deficits and Intervention Tactics

PubMed Central

Hunt, Pamela S.; Barnet, Robert C.

2014-01-01

Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5 g/kg/day ethanol on postnatal days (PD) 4–9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as ‘gap filling’ completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions. PMID:25477227

Acetylcholine release from the rabbit isolated superior cervical ganglion preparation.

PubMed

Dawes, P M; Vizi, E S

1973-06-01

1. The rabbit isolated superior cervical ganglion preparation has been used to measure the release of acetylcholine from the tissue at rest and during preganglionic nerve stimulation.2. In the presence of physostigmine, the resting release of acetylcholine was 0.13 +/- 0.01 (nmol/g)/min (10 experiments) and that during stimulation with 300 shocks at 10 Hz was 3.1 +/- 0.4 (pmol/g)/volley in 4 experiments (means +/- S.E.M.). The volley output was independent of the frequency of stimulation over the range 1 to 10 Hz but was higher at 0.3 Hz.3. Tetrodotoxin, 0.8 muM, had no effect on the resting release of acetylcholine but reduced the stimulated release below detectable levels (2 pmol). Lowering the temperature of the bathing fluid to 5 degrees C reduced to below detectable levels both the resting release and that produced by nerve stimulation.4. The resting release of acetylcholine was increased by a potassium-rich (49.4 mM K(+)) bathing solution and by replacing the sodium chloride in the solution with lithium chloride (113 mM Li(+)).5. (-)-Noradrenaline bitartrate, 3 muM, and (+/-)-adrenaline bitartrate, 1.5 muM, reduced by 70% the output of acetylcholine induced by stimulation at 0.3 Hz, but failed to reduce the resting release or that evoked by stimulation at 10 Hz. The inhibition was reversed by phentolamine.6. It is concluded that the rabbit superior cervical ganglion in vitro is a suitable preparation for studying transmitter release and that the ganglion blocking effect of catecholamines is due to a reduction in transmitter release.

Distribution of cholinesterases in insects*

PubMed Central

Booth, G. M.; Lee, An-Horng

1971-01-01

The study of toxicology and other related fields has been largely based on in vitro techniques. These methods have provided quantitative information on the effects of inhibitors on enzymes, but none on the localized effects of inhibitors on selected sites of action within the animal. Histochemical study of frozen sections does provide data on the site of action of toxicants. The utility of histochemistry in conjunction with in vitro methods is discussed. The substrates acetylthiocholine and phenyl thioacetate were utilized in demonstrating cholinesterase. Neither substrate penetrated well into freshly dissected nerve cord preparations, but both compounds were hydrolysed by sectioned tissue. The leaving group of phenyl thioacetate was demonstrated to be benzenethiol. In general, acetylthiocholine was hydrolysed slightly more rapidly by insect cholinesterases. A unique cholinesterase was found in motor end-plates of cricket muscle, which hydrolyses acetylthiocholine and which was inhibited by physostigmine. No other insect muscle preparation showed this activity. Topical application of insecticides showed that a vital site of action in flies is the peripheral area of the thoracic ganglia and that in crickets the brain and nerve cord are involved at knock-down. Kinetic data indicate that acetylthiocholine has a greater affinity than does phenyl thioacetate for a variety of enzyme sources. Ultrastructural evidence shows that cholinesterases that hydrolyse acetylthiocholine are membrane-bound. Phenyl thioacetate was found to be useful as a model in designing new insecticides. ImagesFig. 5Fig. 6Fig. 7Fig. 8Fig. 13Fig. 14Fig. 15Fig. 16Fig. 9Fig. 10Fig. 11Fig. 12Fig. 1Fig. 2Fig. 3Fig. 4Fig. 17Fig. 18Fig. 19 PMID:5315359

An in vitro investigation of the effects of the nerve agent pretreatment pyridostigmine bromide on human peripheral blood T-cell function.

PubMed

Telford, Gary; Wilkinson, Lucy J; Hooi, Doreen S W; Worrall, Vivienne; Green, A Christopher; Cook, David L; Pritchard, David I; Griffiths, Gareth D

2004-11-01

The current pretreatment against nerve agent poisoning deployed by the UK and US armed forces is the acetylcholinesterase (EC 3.1.1.7) inhibitor pyridostigmine bromide (PB). At higher doses, PB is also used to treat the autoimmune disease myasthenia gravis. In both cases, the therapeutic effect is mediated by inhibition of acetylcholinesterase (AChE) at cholinergic synapses. However, the location of AChE is not restricted to these sites. AChE, acetylcholine (ACh) receptors and choline acetyltransferase have been reported to be expressed by T cells, suggesting that cholinergic signalling may exert some modulatory influence on T-cell function and consequently on the immune system. The aim of this study was to investigate the role of the T-cell cholinergic system in the immunological activation process and to examine whether inhibitors of AChE such as PB affect immune function. To investigate this, human peripheral blood mononuclear cells (PBMC) were stimulated using either mitogen, cross-linking of the T-cell receptor and co-receptors with antibodies (anti-CD3/CD28) or by antigen presentation in the presence of various AChE inhibitors and ACh receptor agonists or antagonist. Several indices were used to assess T-cell activation, including the secretion of IL-2, cell proliferation and expression of CD69. Treatment with PB had no significant effect on the immunological assays selected. Physostigmine (PHY), a carbamate compound similar to PB, consistently showed inhibition of T-cell activation, but only at concentrations in excess of those required to inhibit AChE. No evidence was found to support previously published findings showing muscarinic enhancement of cell proliferation or IL-2 secretion.

[Intoxications with plants].

PubMed

Kupper, Jacqueline; Reichert, Cornelia

2009-05-01

Ingestions of plants rarely lead to life-threatening intoxications. Highly toxic plants, which can cause death, are monkshood (Aconitum sp.), yew (Taxus sp.) and autumn crocus (Colchicum autumnale). Lethal ingestions of monkshood and yew are usually suicides, intoxications with autumn crocus are mostly accidental ingestions of the leaves mistaken for wild garlic (Allium ursinum). Severe intoxications can occur with plants of the nightshade family like deadly nightshade (Atropa belladonna), angel's trumpet (Datura suaveolens) or jimsonweed (Datura stramonium). These plants are ingested for their psychoactive effects. Ingestion of plant material by children most often only causes minor symptoms or no symptoms at all, as children usually do not eat great quantities of the plants. They are especially attracted by the colorful berries. There are plants with mostly cardiovascular effects like monkshood, yew and Digitalis sp. Some of the most dangerous plants belong to this group. Plants of the nightshade family cause an anticholinergic syndrome. With golden chain (Laburnum anagyroides), castor bean (Ricinus communis) and raw beans (Phaseolus vulgaris) we see severe gastrointestinal effects. Autumn crocus contains a cell toxin, colchicine, which leads to multiorgan failure. Different plants are irritative or even caustic to the skin. Treatment is usually symptomatic. Activated charcoal is administered within one hour after ingestion (1 g/kg). Endoscopic removal of plant material can be considered with ingestions of great quantities of highly toxic plants. Administration of repeated doses of charcoal (1-2 g/h every 2-4 hours) may be effective in case of oleander poisoning. There exist only two antidotes: Anti-digoxin Fab fragments can be used with cardenolide glycoside-containing plants (Digitalis sp., Oleander). Physostigmine is the antidote for severe anticholinergic symptoms of the CNS. Antibodies against colchicine, having been developed in France, are not available at the moment.

Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes

PubMed Central

Bell, L. Andrew; Bell, Karen A.; McQuiston, A. Rory

2013-01-01

Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K+ channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function in the treatment of some neurodegenerative diseases. PMID:23747570

Acetylcholine release from the rabbit isolated superior cervical ganglion preparation

PubMed Central

Dawes, P. M.; Vizi, E. S.

1973-01-01

1. The rabbit isolated superior cervical ganglion preparation has been used to measure the release of acetylcholine from the tissue at rest and during preganglionic nerve stimulation. 2. In the presence of physostigmine, the resting release of acetylcholine was 0·13 ± 0·01 (nmol/g)/min (10 experiments) and that during stimulation with 300 shocks at 10 Hz was 3·1 ± 0·4 (pmol/g)/volley in 4 experiments (means ± S.E.M.). The volley output was independent of the frequency of stimulation over the range 1 to 10 Hz but was higher at 0·3 Hz. 3. Tetrodotoxin, 0·8 μM, had no effect on the resting release of acetylcholine but reduced the stimulated release below detectable levels (2 pmol). Lowering the temperature of the bathing fluid to 5° C reduced to below detectable levels both the resting release and that produced by nerve stimulation. 4. The resting release of acetylcholine was increased by a potassium-rich (49·4 mM K+) bathing solution and by replacing the sodium chloride in the solution with lithium chloride (113 mM Li+). 5. (-)-Noradrenaline bitartrate, 3 μM, and (±)-adrenaline bitartrate, 1·5 μM, reduced by 70% the output of acetylcholine induced by stimulation at 0·3 Hz, but failed to reduce the resting release or that evoked by stimulation at 10 Hz. The inhibition was reversed by phentolamine. 6. It is concluded that the rabbit superior cervical ganglion in vitro is a suitable preparation for studying transmitter release and that the ganglion blocking effect of catecholamines is due to a reduction in transmitter release. PMID:4733726

The neuroinflammatory phenotype in a mouse model of Gulf War Illness is unrelated to brain regional levels of acetylcholine as measured by quantitative HILIC-UPLC-MS/MS.

PubMed

Miller, Julie V; LeBouf, Ryan F; Kelly, Kimberly A; Michalovicz, Lindsay T; Ranpara, Anand; Locker, Alicia R; Miller, Diane B; O'Callaghan, James P

2018-05-28

Many veterans of the 1991 Persian Gulf War (GW) returned with a chronic multisymptom illness that has been termed Gulf War Illness (GWI). Previous GWI studies have suggested that exposure to acetylcholinesterase inhibitors (AChEIs) in theater, such as sarin and/or pesticides, may have contributed to the symptomatology of GWI. Additionally, concomitant high physiological stress experienced during the war may have contributed to the initiation of the GWI phenotype. While inhibition of AChE leading to accumulation of acetylcholine (ACh) will activate the cholinergic anti-inflammatory pathway, the signature symptomatology of GWI has been shown to be associated with neuroinflammation. To investigate the relationship between ACh and neuroinflammation in discrete brain regions, we used our previously established mouse model of GWI, which combines an exposure to a high physiological stress mimic, corticosterone (CORT), with GW-relevant AChEIs. The AChEIs used in this study were diisopropyl fluorophosphate (DFP), chlorpyrifos oxon (CPO), and physostigmine (PHY). After AChEI exposure, ACh concentrations for cortex (CTX), hippocampus (HIP), and striatum (STR) were determined using hydrophilic interaction liquid chromatography (HILIC) with ultra-performance liquid chromatography (UPLC)-tandem-mass spectrometry (MS/MS). CORT pretreatment ameliorated the DFP-induced ACh increase in HIP and STR, but not CTX. CORT pretreatment did not significantly alter ACh levels for CPO and PHY. Further analysis of STR neuroinflammatory biomarkers revealed an exacerbated CORT+AChEI response, which does not correspond to measured brain ACh. By utilizing this new analytical method for discrete brain region analysis of ACh, this work suggests the exacerbated neuroinflammatory effects in our mouse model of GWI are not driven by the accumulation of brain region-specific ACh.

Timing of decontamination and treatment in case of percutaneous VX poisoning: a mini review.

PubMed

Joosen, Marloes J A; van der Schans, Marcel J; Kuijpers, Willem C; van Helden, Herman P M; Noort, Daan

2013-03-25

Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin. The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent. Repeated administration of these drugs showed to improve treatment efficacy compared to a single injection treatment. Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure. Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs. These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen. Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure. To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4× LD50 VX in IPA. The results showed that RSDL decontamination at 15 min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment. A similar decontamination regimen with RSDL at 90 min showed that it still might effectively increase the time window of opportunity for treatment. In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment. The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Effects of tachykinin receptor agonists and antagonists on the guinea-pig isolated oesophagus.

PubMed

Kerr, K P

2000-11-01

1. Vagal nerve stimulation of the guinea-pig isolated oesophagus produced a triphasic tetrodotoxin (TTX)-sensitive contractile response. The third phase, which was resistant to ganglion blocking drugs, was selectively abolished by capsaicin, suggesting the involvement of one or more neuropeptides released from afferent neurons. Receptors on cholinergic neurons were subsequently activated because the response was atropine sensitive. Contractile responses resulting from exogenous substance P were abolished by atropine and TTX and enhanced by physostigmine. These findings suggest that the third phase may be mediated by the action of a substance P-like neuropeptide released from sensory nerve endings that subsequently activated cholinergic neurons. 2. The tachykinin receptors in the body of the guinea-pig oesophagus were characterized by determining the relative agonist potencies of natural tachykinins as well as tachykinin receptor-selective analogues. Antagonist affinities were also determined. The results indicated the presence of both NK2 and NK3 receptors. In addition, the effects of a cocktail of peptidase inhibitors (captopril, thiorphan and amastatin) on responses to various tachykinins and synthetic analogues were determined. The results indicate that one or more peptidases are present in this preparation. 3. Experiments using various tachykinin receptor antagonists were performed to determine whether the activation of tachykinin receptors played a role in the mediation of the third phase of the response to vagal nerve stimulation. While this response was unaffected by NK1 and NK2 receptor-selective antagonists, it was only partially inhibited (23%) by the NK3 receptor antagonist SR 142801. Thus, in the guinea-pig oesophagus, it appears that NK3 receptors play only a minor role in mediating a contractile response when afferent neurons are excited by vagal nerve stimulation.

Effects of drugs affecting endogenous amines or cyclic nucleotides on ethanol withdrawal head twitches in mice.

PubMed Central

Collier, H O; Hammond, M D; Schneider, C

1976-01-01

1 Twenty-four hours after ethanol withdrawal, dependent mice exhibited frequent head twitching. Naive mice exhibited similar twitching 15 min after treatment with 5-hydroxytryptophan (5-HTP) or 6 h after alpha-methyl-p-tyrosine (AMPT). Ethanol lessened the incidence of head twitches induced by any of these treatments. 5-HTP and AMPT each increased the incidence of head twitches induced by withdrawal of ethanol from dependent mice. 2 Drugs that affect the amount or activity of endogenous amines or cyclic nucleotides modified the incidence of head twitches. Nearly all drugs acted in the same direction on twitching elicited by any of these three treatments. 3 The incidence was lessened by: (a) methysergide, methergoline, MA 1420, p-chlorophenylalanine and p-chloroamphetamine; (b) dopamine, noradrenaline, L-DOPA, amphetamine and apomorphine; (c) hyoscine and nicotine; and (d) adenosine triphosphate, dibutyryl cyclic adenosine-3',5'-monophosphate (db cyclic AMP) and prostaglandins E1 and E2. 4 The incidence was increased by: (a) acetylcholine, carbachol and physostigmine; and (b) guanosine triphosphate, dibutyryl cyclic guanosine monophosphate (db cyclic GMP), theophylline and 3-isobutyl-1-methyl-xanthine. 5 These findings suggest that head twitching induced by these three treatments arises from a common biochemical mechanism, which may ultimately be a change in favour of cyclic GMP of the balance between this nucleotide and cyclic AMP within appropriate neurones. This imbalance appears to be elicited or increased by 5-hydroxytryptamine and acetylcholine and to be decreased by dopamine, noradrenaline and E prostaglandins. 6 Neither actinomycin D nor cycloheximide, given during the induction of ethanol dependence, altered the incidence of head twitches after ethanol withdrawal. PMID:987821

Composition and cytotoxic and antioxidant activities of the oil of Piper aequale Vahl.

PubMed

da Silva, Joyce Kelly R; Pinto, Laine C; Burbano, Rommel M R; Montenegro, Raquel C; Andrade, Eloísa Helena A; Maia, José Guilherme S

2016-10-07

Piper aequale Vahl is a small shrub that grows in the shadow of large trees in the Carajás National Forest, Municipality of Parauapebas, Para state, Brazil. The local people have used the plant against rheumatism and inflammation. The essential oil of the aerial parts was extracted and analyzed by GC and GC-MS. The MTT colorimetric assay was used to measuring the cytotoxic activity of the oil against human cancer lines. The determination of antioxidant activity of the oil was conducted by DPPH radical scavenging assay. The main constituents were δ-elemene (18.92 %), β-pinene (15.56 %), α-pinene (12.57 %), cubebol (7.20 %), β-atlantol (5.87 %), and bicyclogermacrene (5.51 %), totalizing 65.63 % of the oil. The oil displayed a strong in vitro cytotoxic activity against the human cancer cell lines HCT-116 (colon) and ACP03 (gastric) with IC 50 values of 8.69 μg/ml and 1.54 μg/ml, respectively. The oil has induced the apoptosis in a gastric cancer cells in all tested concentration (0.75-3.0 μg/ml), after 72 h of treatment, when compared to negative control (p < 0.001). Also, the oil showed a significant antioxidant activity (280.9 ± 22.2 mg TE/ml), when analyzed as Trolox equivalent, and a weak acetylcholinesterase inhibition, with a detection limit of 100 ng, when compared to the physostigmine standard (1.0 ng). The higher cell growth inhibition induced by the oil of P. aequale is probably due to its primary terpene compounds, which were previously reported in the proliferation inhibition, in stimulation of apoptosis and induction of cell cycle arrest in malignant cells.

Use of ferric chloride to identify salicylate-containing poisons.

PubMed

Hoffman, Robert J; Nelson, Lewis S; Hoffman, Robert S

2002-01-01

Ferric chloride (FeCl3) is used to qualitatively test the urine of patients with presumed salicylate exposure. FeCl3 testing of an unidentified poison might provide evidence of salicylate exposure in situations where FeCl3 urine testing cannot be used. Such situations include the absence of a urine sample, immediately after ingestion before urine contains a detectable quantity of salicylate, or for patients chronically using salicylatesfor which FeCl3 testing is unhelpful. This study seeks to determine if FeCl3 can be used to identify salicylate-containing products. We assessed the reactivity of FeCl3 with commercially available salicylate-containing products. We applied 0.1 mL of 10% FeCl3 solution to each of 15 various salicylate-containing products including: regular and buffered acetylsalicylic acid, bismuth subsalicylate, methylsalicylate, physostigmine salicylate, salicylic acid, trolamine salicylate, and herbal tablets with salicin-containing white willow bark (Salix sp.). These products tested were: regular and enteric-coatedpills (n = 4), powder (n = 1), topical creams (n = 5), topical liquids (n = 4), and intravenous solution (n = 1). FeCl3 was applied to crushed tablets and added directly to liquids and creams. Fifteen salicylate-free controls including liquids, pills, and creams similar in appearance to experimental samples were also tested. Three blinded physiciansfamiliar with FeCl3 testing independently observed the addition of FeCl3 to each sample and rated a positive or negative result. All salicylate-containing products were interpreted to be clearly FeCl3 positive and all control samples were interpreted to be clearly FeCl3 negative. Salicylate-containing products may be identified using FeCl33. When using FeCl3

Acetylcholinesterase inhibition and locomotor function after motor-sensory cortex impact injury.

PubMed

Holschneider, Daniel P; Guo, Yumei; Roch, Margareth; Norman, Keith M; Scremin, Oscar U

2011-09-01

Traumatic brain injury (TBI) induces transient or persistent dysfunction of gait and balance. Enhancement of cholinergic transmission has been reported to accelerate recovery of cognitive function after TBI, but the effects of this intervention on locomotor activity remain largely unexplored. The hypothesis that enhancement of cholinergic function by inhibition of acetylcholinesterase (AChE) improves locomotion following TBI was tested in Sprague-Dawley male rats after a unilateral controlled cortical impact (CCI) injury of the motor-sensory cortex. Locomotion was tested by time to fall on the constant speed and accelerating Rotarod, placement errors and time to cross while walking through a horizontal ladder, activity monitoring in the home cages, and rearing behavior. Assessments were performed the 1st and 2nd day and the 1st, 2nd, and 3rd week after TBI. The AChE inhibitor physostigmine hemisulfate (PHY) was administered continuously via osmotic minipumps implanted subcutaneously at the rates of 1.6-12.8 μmol/kg/day. All measures of locomotion were impaired by TBI and recovered to initial levels between 1 and 3 weeks post-TBI, with the exception of the maximum speed achievable on the accelerating Rotarod, as well as rearing in the open field. PHY improved performance in the accelerating Rotarod at 1.6 and 3.2 μmol/kg/day (AChE activity 95 and 78% of control, respectively), however, higher doses induced progressive deterioration. No effect or worsening of outcomes was observed at all PHY doses for home cage activity, rearing, and horizontal ladder walking. Potential benefits of cholinesterase inhibition on locomotor function have to be weighed against the evidence of the narrow range of useful doses.

Planarian cholinesterase: in vitro characterization of an evolutionarily ancient enzyme to study organophosphorus pesticide toxicity and reactivation.

PubMed

Hagstrom, Danielle; Hirokawa, Hideto; Zhang, Limin; Radic, Zoran; Taylor, Palmer; Collins, Eva-Maria S

2017-08-01

The freshwater planarian Dugesia japonica has recently emerged as an animal model for developmental neurotoxicology and found to be sensitive to organophosphorus (OP) pesticides. While previous activity staining of D. japonica, which possess a discrete cholinergic nervous system, has shown acylthiocholine catalysis, it is unknown whether this is accomplished through an acetylcholinesterase (AChE), butyrylcholinesterase (BChE), or a hybrid esterase and how OP exposure affects esterase activity. Here, we show that the majority of D. japonica cholinesterase (DjChE) activity departs from conventional AChE and BChE classifications. Inhibition by classic protonable amine and quaternary reversible inhibitors (ethopropazine, donepezil, tacrine, edrophonium, BW284c51, propidium) shows that DjChE is far less sensitive to these inhibitors than human AChE, suggesting discrete differences in active center and peripheral site recognition and structures. Additionally, we find that different OPs (chlorpyrifos oxon, paraoxon, dichlorvos, diazinon oxon, malaoxon) and carbamylating agents (carbaryl, neostigmine, physostigmine, pyridostigmine) differentially inhibit DjChE activity in vitro. DjChE was most sensitive to diazinon oxon and neostigmine and least sensitive to malaoxon and carbaryl. Diazinon oxon-inhibited DjChE could be reactivated by the quaternary oxime, pralidoxime (2-PAM), and the zwitterionic oxime, RS194B, with RS194B being significantly more potent. Sodium fluoride (NaF) reactivates OP-DjChE faster than 2-PAM. As one of the most ancient true cholinesterases, DjChE provides insight into the evolution of a hybrid enzyme before the separation into distinct AChE and BChE enzymes found in higher vertebrates. The sensitivity of DjChE to OPs and capacity for reactivation validate the use of planarians for OP toxicology studies.

First and second generation antipsychotics influence hippocampal gamma oscillations by interactions with 5-HT3 and D3 receptors

PubMed Central

Schulz, Steffen B; Heidmann, Karin E; Mike, Arpad; Klaft, Zin-Juan; Heinemann, Uwe; Gerevich, Zoltan

2012-01-01

BACKGROUND AND PURPOSE Disturbed cortical gamma band oscillations (30–80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease. EXPERIMENTAL APPROACH Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices. KEY RESULTS Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pKi values for 19 receptors and analysed for correlation. Our results indicated that 5-HT3 receptors have an enhancing effect on gamma oscillations whereas dopamine D3 receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT3, D3 and 5-HT2C receptors were applied and revealed that 5-HT3 receptors indeed enhanced the gamma power whereas D3 receptors reduced it. As predicted, 5-HT2C receptors had no effects on gamma oscillations. CONCLUSION AND IMPLICATIONS Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT3 and dopamine D3 receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs. PMID:22817643

The role of the cholinergic system in the signal attenuation rat model of obsessive-compulsive disorder.

PubMed

Yankelevitch-Yahav, Roni; Roni, Yankelevitch-Yahav; Joel, Dapha; Daphna, Joel

2013-11-01

In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive-compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse. The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, "compulsive" behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15 mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00 mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8 mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300 mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50 mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10). Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro-compulsive effect in the signal attenuation model. Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD.

Modulation of release of [3H]acetylcholine in the major pelvic ganglion of the rat.

PubMed

Somogyi, G T; de Groat, W C

1993-06-01

Cholinergic modulation of [3H]acetylcholine release evoked by electrical stimulation was studied in the rat major pelvic ganglion, which was prelabeled with [3H]choline. Acetylcholine (ACh) release was independent of the frequency of stimulation; 0.3 Hz produced the same volley output as 10 Hz. Tetrodotoxin (1 microM) or omission of Ca2+ from the medium abolished ACh release. The M1 receptor agonist (4-hydroxy-2-butynyl)-1-trimethylammonium m-chlorocarbanilate chloride (McN-A 343, 50 microM) increased release (by 136%), whereas the M2 muscarinic agonist oxotremorine (1 microM) decreased ACh release (by 22%). The muscarinic antagonists, atropine (1 microM) or pirenzepine (M1 selective, 1 microM), did not change ACh release. However, pirenzepine (1 microM) blocked the facilitatory effect of McN-A 343, and atropine (1 microM) blocked the inhibitory effect of oxotremorine. The cholinesterase inhibitor physostigmine (1-5 microM), the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP, 10 microM), and the nicotinic antagonist D-tubocurarine (50 microM) did not change ACh release. 4-Aminopyridine, a K+ channel blocker, significantly increased the release (by 146%). Seven days after decentralization of the major pelvic ganglion, the evoked release of ACh was abolished. It is concluded that release of ACh occurs from the preganglionic nerve terminals rather than from the cholinergic cell bodies and is not modulated by actions of endogenous ACh on either muscarinic or nicotinic autoreceptors. These data confirm and extend previous electrophysiological findings indicating that synapses in the major pelvic ganglion have primarily a relay function.

Screening approach by ultra-high performance liquid chromatography-tandem mass spectrometry for the blood quantification of thirty-four toxic principles of plant origin. Application to forensic toxicology.

PubMed

Carlier, Jérémy; Guitton, Jérôme; Romeuf, Ludovic; Bévalot, Fabien; Boyer, Baptiste; Fanton, Laurent; Gaillard, Yvan

2015-01-15

Plant poisonings have left their mark on history and still cause many deaths, whether intentional or accidental. The means to show toxicological evidence of such poisonings should be implemented with great care. This article presents a technique for measuring thirty-nine toxic principles of plant origin in the blood, covering a large amount of toxins from local or exotic plants: α-lobeline, α-solanine, aconitine, ajmaline, atropine, brucine, cephalomannine, colchicine, convallatoxin, cymarine, cytisine, digitoxin, digoxin, emetine, gelsemine, ibogaine, jervine, kavain, lanatoside C, lupanine, mitragynine, neriifolin, oleandrin, ouabain, paclitaxel, physostigmine, pilocarpine, podophyllotoxin, proscillaridin A, reserpine, retrorsine, ricinine, scopolamine, senecionine, sparteine, strophanthidin, strychnine, veratridine and yohimbine. Analysis was carried out using an original ultra-high performance liquid chromatography separation coupled with tandem mass spectrometry detection. Extraction was a standard solid phase extraction performed on Oasis(®) HLB cartridge. Thirty-four of the thirty-nine compounds were put through a validation procedure. The assay was linear in the calibration curve range from 0.5 or 5 μg/L to 1000 μg/L according to the compounds. The method is sensitive (LOD from 0.1 to 1.6 μg/L). The within-day precision of the assay was less than 22.5% at the LLOQ, and the between-day precision was less than 21.5% for 10 μg/L for all the compounds included. The assay accuracy was in the range of 87.4 to 119.8% for the LLOQ. The extraction recovery and matrix effect ranged from 30 to 106% and from -30 to 14%, respectively. It has proven useful and effective in several difficult forensic cases. Copyright © 2014 Elsevier B.V. All rights reserved.

A T-cell-dependent humoral immune response is preserved during the administration of the nerve agent pre-treatment pyridostigmine bromide in a murine model.

PubMed

Griffiths, Gareth D; Telford, Gary; Hooi, Doreen S W; Cook, David L; Wilkinson, Lucy J; Green, Christopher A; Pritchard, David I

2005-03-01

Immune regulation, either via the autonomic nervous system or by a proposed "non-neuronal" cholinergic system, suggests that the immune system may be susceptible to perturbation by compounds affecting cholinergic function. Here, the current UK and US nerve agent pre-treatment, pyridostigmine bromide (PB) and the related anti-acetylcholinesterase (AChE) compounds physostigmine (PHY) and BW284c51 were tested for their ability to affect mouse splenocyte function in vitro. In addition, PB, at a dose equivalent to that received during pre-treatment for nerve agent poisoning, was tested for its effect on a T-cell-dependent humoral response to antigen in vivo in the mouse. None of the anti-AChEs tested affected concanavalin A (Con A)-, anti-CD3- or lipopolysaccharide LPS-driven splenocyte proliferation, in vitro, at concentrations expected to give effective nerve agent pre-treatment. However, higher concentrations (>100 microM) particularly of PHY caused some inhibition of the proliferative responses. In vivo, PB or saline was administered via 28-day mini-osmotic pumps to give a 25-40% inhibition of whole blood AChE in the PB-treated animals. During PB or saline administration, primary and secondary doses (i.p.) of sheep red blood cells (SRBC) were given and the humoral response determined by monitoring anti-SRBC IgM and IgG levels. Splenocytes isolated from the experimental animals were also examined for their proliferative and cytokine responses to stimulation. No remarkable effects of PB were seen during the period of AChE inhibition on the humoral immune response. However, a modest elevation in IL-2 and IFN(gamma) in Con A-stimulated lymphocytes was seen in PB-treated animals following pump removal. Overall these data suggest that, in vivo, the SRBC stimulated T-cell-dependent immune response is unaffected by the administration of PB at pre-treatment doses.

Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release.

PubMed

Chávez, Jaime; Segura, Patricia; Vargas, Mario H; Arreola, José Luis; Flores-Soto, Edgar; Montaño, Luis M

2007-04-01

Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca2+) measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, omega-conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of approximately 50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M2- or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca2+ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX- and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the stimulation of M2 receptors; and 3) after this transient salbutamol-induced relaxation, a paradoxical contraction ensues due to the subsequent release of substance P.

In vivo neurochemical evidence that delta1-, delta2- and mu2-opioid receptors, but not mu1-opioid receptors, inhibit acetylcholine efflux in the nucleus accumbens of freely moving rats.

PubMed

Kiguchi, Yuri; Aono, Yuri; Watanabe, Yuriko; Yamamoto-Nemoto, Seiko; Shimizu, Kunihiko; Shimizu, Takehiko; Kosuge, Yasuhiro; Waddington, John L; Ishige, Kumiko; Ito, Yoshihisa; Saigusa, Tadashi

2016-10-15

Cholinergic neurons in the nucleus accumbens express delta- and mu-opioid receptors that are thought to inhibit neural activity. Delta- and mu-opioid receptors are divided into delta1- and delta2-opioid receptors and mu1- and mu2-opioid receptors, respectively. We analysed the roles of delta- and mu-opioid receptor subtypes in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. Other than naloxonazine, given intraperitoneally, delta- and mu-opioid receptor ligands were administered intracerebrally through the dialysis probe. Doses of these compounds indicate total amount (mol) over an infusion time of 30-60min. To monitor basal acetylcholine, a low concentration of physostigmine (50nM) was added to the perfusate. The delta1-opioid receptor agonist DPDPE (3 and 300pmol) and delta2-opioid receptor agonist deltorphin II (3 and 30pmol) decreased accumbal acetylcholine in a dose-related manner. DPDPE (300pmol)- and deltorphin II (3pmol)-induced reductions in acetylcholine were each inhibited by the delta1-opioid receptor antagonist BNTX (0.3pmol) and delta2-opioid receptor antagonist naltriben (15pmol), respectively. The mu-opioid receptor agonists endomorphin-1 and endomorphin-2 (6 and 30nmol) decreased acetylcholine in a dose-related manner. Endomorphin-1- and endomorphin-2 (30nmol)-induced reductions in acetylcholine were prevented by the mu-opioid receptor antagonist CTOP (3nmol). The mu1-opioid receptor antagonist naloxonazine (15mg/kg ip), which inhibits endomorphin-1 (15nmol)-induced accumbal dopamine efflux, did not alter endomorphin-1- or endomorphin-2 (30nmol)-induced reductions in acetylcholine efflux. This study provides in vivo evidence for delta1-, delta2- and mu2-opioid receptors, but not mu1-opioid receptors, that inhibit accumbal cholinergic neural activity. Copyright © 2016 Elsevier B.V. All rights reserved.

Desformylflustrabromine (dFBr) and [3H]dFBr-Labeled Binding Sites in a Nicotinic Acetylcholine Receptor

PubMed Central

Hamouda, Ayman K.; Wang, Ze-Jun; Stewart, Deirdre S.; Jain, Atul D.; Glennon, Richard A.

2015-01-01

Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) of α4β2 and α2β2 nAChRs that, at concentrations >1 µM, also inhibits these receptors and α7 nAChRs. However, its interactions with muscle-type nAChRs have not been characterized, and the locations of its binding site(s) in any nAChR are not known. We report here that dFBr inhibits human muscle (αβεδ) and Torpedo (αβγδ) nAChR expressed in Xenopus oocytes with IC50 values of ∼1 μM. dFBr also inhibited the equilibrium binding of ion channel blockers to Torpedo nAChRs with higher affinity in the nAChR desensitized state ([3H]phencyclidine; IC50 = 4 μM) than in the resting state ([3H]tetracaine; IC50 = 60 μM), whereas it bound with only very low affinity to the ACh binding sites ([3H]ACh, IC50 = 1 mM). Upon irradiation at 312 nm, [3H]dFBr photoincorporated into amino acids within the Torpedo nAChR ion channel with the efficiency of photoincorporation enhanced in the presence of agonist and the agonist-enhanced photolabeling inhibitable by phencyclidine. In the presence of agonist, [3H]dFBr also photolabeled amino acids in the nAChR extracellular domain within binding pockets identified previously for the nonselective nAChR PAMs galantamine and physostigmine at the canonical α-γ interface containing the transmitter binding sites and at the noncanonical δ-β subunit interface. These results establish that dFBr inhibits muscle-type nAChR by binding in the ion channel and that [3H]dFBr is a photoaffinity probe with broad amino acid side chain reactivity. PMID:25870334

Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention

PubMed Central

Ricciardi, Emiliano; Handjaras, Giacomo; Bernardi, Giulio; Pietrini, Pietro; Furey, Maura L.

2012-01-01

Enhancing cholinergic function improves performance on various cognitive tasks and alters neural responses in task specific brain regions. Previous findings by our group strongly suggested that the changes in neural activity observed during increased cholinergic function may reflect an increase in neural efficiency that leads to improved task performance. The current study was designed to assess the effects of cholinergic enhancement on regional brain connectivity and BOLD signal variability. Nine subjects participated in a double-blind, placebo-controlled crossover functional magnetic resonance imaging (fMRI) study. Following an infusion of physostigmine (1mg/hr) or placebo, echo-planar imaging (EPI) was conducted as participants performed a selective attention task. During the task, two images comprised of superimposed pictures of faces and houses were presented. Subjects were instructed periodically to shift their attention from one stimulus component to the other and to perform a matching task using hand held response buttons. A control condition included phase-scrambled images of superimposed faces and houses that were presented in the same temporal and spatial manner as the attention task; participants were instructed to perform a matching task. Cholinergic enhancement improved performance during the selective attention task, with no change during the control task. Functional connectivity analyses showed that the strength of connectivity between ventral visual processing areas and task-related occipital, parietal and prefrontal regions was reduced significantly during cholinergic enhancement, exclusively during the selective attention task. Cholinergic enhancement also reduced BOLD signal temporal variability relative to placebo throughout temporal and occipital visual processing areas, again during the selective attention task only. Together with the observed behavioral improvement, the decreases in connectivity strength throughout task-relevant regions and BOLD variability within stimulus processing regions provide further support to the hypothesis that cholinergic augmentation results in enhanced neural efficiency. PMID:22906685

Cholinergic modulation of the parafacial respiratory group

PubMed Central

Boutin, Rozlyn C. T.; Alsahafi, Zaki

2016-01-01

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. PMID:27808424

Cholinesterase activity in the cup oyster Saccostrea sp. exposed to chlorpyrifos, imidacloprid, cadmium and copper.

PubMed

Moncaleano-Niño, Angela M; Luna-Acosta, Andrea; Gómez-Cubillos, Maria Camila; Villamil, Luisa; Ahrens, Michael J

2018-04-30

In the present study, the sensitivity and concentration dependence of three functionally-defined components of cholinesterase activity (total: T-ChE; eserine-sensitive: Es-ChE; and eserine-resistant: Er-ChE) were quantified in the gill, digestive gland and adductor muscle of the tropical cup oyster Saccostrea sp., following acute (96h) aqueous exposure to commercial formulations of the organophosphate (OP) insecticide chlorpyrifos and the neonicotinoid (NN) imidacloprid (concentration range: 0.1-100mg/L), as well as to dissolved cadmium and copper (concentration range: 1-1000μg/L). Oysters (1.5-5.0cm shell length), field-collected from a boating marina in Santa Marta, Colombia (Caribbean Sea) were exposed in the laboratory to each substance at five concentrations. T-ChE, Es-ChE, and Er-ChE activity were quantified in the three tissues in pools of 5 individuals (3 replicates per concentration), before and after inhibition with the total cholinesterase inhibitor eserine (physostigmine, 100µM). Oysters exposed to chlorpyrifos, imidacloprid and Cd showed reduced T-ChE and Es-ChE activity in gills at highest exposure concentrations, with Es-ChE activity being inhibited proportionally more so than T-ChE, whereas Er-ChE activity showed no significant concentration-response. Digestive gland also showed diminished T-ChE, Es-ChE and Er-ChE activity for highest chlorpyrifos and Cd concentrations relative to controls, but an increase of T-ChE and Er-ChE activity at the highest imidacloprid concentration (100mg/L). For Cu, T-ChE, Es-ChE and Er-ChE activities in gills and digestive gland were elevated relative to controls in oysters exposed to Cu concentrations > 100µg/L. In adductor muscle, T-ChE, Es-ChE and Er-ChE activity showed no apparent pattern for any of the four xenobiotics and concentration levels tested. Although this study confirms acute (96h) concentration-dependent reduction of tissue T-ChE and Es-ChE activity in gills and digestive glands of Saccostrea sp. exposed to high concentrations of chlorpyrifos (100mg/L), significant changes in T-ChE, Es-ChE and Er-ChE were also caused by exposure to Cd and Cu at concentrations > 100µg/L and by exposure to imidacloprid (100mg/L), indicating that cholinesterase activity is not a specific biomarker of organophosphate exposure in this species, but, rather, a biomarker of diverse xenobiotic exposure. Copyright © 2018 Elsevier Inc. All rights reserved.

Cholinergic medication for antipsychotic-induced tardive dyskinesia.

PubMed

Tammenmaa-Aho, Irina; Asher, Rosie; Soares-Weiser, Karla; Bergman, Hanna

2018-03-19

Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD. To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness. An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations. We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials. Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life. TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.

The Toxicology Investigators Consortium Case Registry--the 2012 experience.

PubMed

Wiegand, Timothy; Wax, Paul; Smith, Eric; Hart, Katherine; Brent, Jeffrey

2013-12-01

In 2010, the American College of Medical Toxicology (ACMT) established its Case Registry, the Toxicology Investigators Consortium (ToxIC). All cases are entered prospectively and include only suspected and confirmed toxic exposures cared for at the bedside by board-certified or board-eligible medical toxicologists at its participating sites. The primary aims of establishing this Registry include the development of a realtime toxico-surveillance system in order to identify and describe current or evolving trends in poisoning and to develop a research tool in toxicology. ToxIC allows for extraction of data from medical records from multiple sites across a national and international network. All cases seen by medical toxicologists at participating institutions were entered into the database. Information characterizing patients entered in 2012 was tabulated and data from the previous years including 2010 and 2011 were included so that cumulative numbers and trends could be described as well. The current report includes data through December 31st, 2012. During 2012, 38 sites with 68 specific institutions contributed a total of 7,269 cases to the Registry. The total number of cases entered into the Registry at the end of 2012 was 17,681. Emergency departments remained the most common source of consultation in 2012, accounting for 61 % of cases. The most common reason for consultation was for pharmaceutical overdose, which occurred in 52 % of patients including intentional (41 %) and unintentional (11 %) exposures. The most common classes of agents were sedative-hypnotics (1,422 entries in 13 % of cases) non-opioid analgesics (1,295 entries in 12 % of cases), opioids (1,086 entries in 10 % of cases) and antidepressants (1,039 entries in 10 % of cases). N-acetylcysteine (NAC) was the most common antidote administered in 2012, as it was in previous years, followed by the opioid antagonist naloxone, sodium bicarbonate, physostigmine and flumazenil. Anti-crotalid Fab fragments were administered in 109 cases or 82 % of cases in which a snake envenomation occurred. There were 57 deaths reported in the Registry in 2012. The most common associated agent alone or in combination was the non-opioid analgesic acetaminophen, being reported in 10 different cases. Other common agents and agent classes involved in death cases included ethanol, opioids, the anti-diabetic agent metformin, sedatives-hypnotics and cardiovascular agents, in particular amlodipine. There were significant trends identified during 2012. Abuse of over-the-counter medications such as dextromethorphan remains prevalent. Cases involving dextromethorphan continued to be reported at frequencies higher than other commonly abused drugs including many stimulants, phencyclidine, synthetic cannabinoids and designer amphetamines such as bath salts. And, while cases involving synthetic cannabinoids and psychoactive bath salts remained relatively constant from 2011 to 2012 several designer amphetamines and novel psychoactive substances were first reported in the Registry in 2012 including the NBOME compounds or "N-bomb" agents. LSD cases also spiked dramatically in 2012 with an 18-fold increase from 2011 although many of these cases are thought to be ultra-potent designer amphetamines misrepresented as "synthetic" LSD. The 2012 Registry included over 400 Adverse Drug Reactions (ADRs) involving 4 % of all Registry cases with 106 agents causing at least 2 ADRs. Additional data including supportive cares, decontamination, and chelating agent use are also included in the 2012 annual report. The Registry remains a valuable toxico-surveillance and research tool. The ToxIC Registry is a unique tool for identifying and characterizing confirmed cases of significant or potential toxicity or complexity to require bedside care by a medical toxicologist.

The Toxicology Investigators Consortium Case Registry--the 2011 experience.

PubMed

Wiegand, Timothy J; Wax, Paul M; Schwartz, Tayler; Finkelstein, Yaron; Gorodetsky, Rachel; Brent, Jeffrey

2012-12-01

In 2010, the American College of Medical Toxicology established its Case Registry, the Toxicology Investigators Consortium (ToxIC). ToxIC is a prospective registry, which exclusively compiles suspected and confirmed toxic exposure cases cared for at the bedside by medical toxicologists at its participating sites. The Registry aims to fulfill two important gaps in the field: a real-time toxicosurveillance system to identify current poisoning trends and a powerful research tool in toxicology. ToxIC allows extraction of information from medical records making it the most robust multicenter database on chemical toxicities in existence. All cases seen by medical toxicologists at participating institutions were entered in a database. Information characterizing patients entered in 2011 was tabulated. 2010 data was also included so that cumulative total numbers could be described as well. The current report is a summary of the data collected in 2011 in comparison to 2010 entries and also includes cumulative data through December 31st, 2011. During 2011, 28 sites with 49 specific institutions contributed a total of 6,456 cases to the Registry. The total number of cases entered into the registry at the end of 2011 was 10,392. Emergency departments remained the most common source of consultations in 2011, accounting for 53 % of cases. The most common reason for consultation was for pharmaceutical overdoses, which occurred in 48 % of patients, including intentional (37 %) and unintentional (11 %) exposures. The most common classes of agents were sedative-hypnotics (1,492 entries in 23 % of cases), non-opioid analgesics (1,368 cases in 21 % of cases), opioids (17 %), antidepressants (16 %), stimulants/sympathomimetics (12 %), and ethanol (8 %). N-acetylcysteine was the most commonly administered antidote during 2011, similar to 2010, followed by the opioid antagonist naloxone, sodium bicarbonate, physostigmine and flumazenil. Anti-crotalid Fab fragments (CroFab) were administered in 106 out of 131 cases in which an envenomation occurred. There were 35 deaths recorded in the Registry during 2011. The most common associated agents, including when reported as sole agent or in combination with other agents, were opioids and analgesics (acetaminophen, aspirin, NSAIDS) with ten and eight deaths, respectively. Oxycodone was reported in six of the ten opioid-related deaths and heroin in three. Acetaminophen was the most common single agent reported overall being identified in all eight of the death cases attributed to analgesics. There were significant trends identified during 2011. Cases involving designer drugs including psychoactive bath salts and synthetic cannabinoids increased substantially from 2010 to 2011. The psychoactive bath salts were responsible for a large increase in stimulant/sympathomimetic-related cases reported to the Registry in 2011 with overall numbers doubling from 6 % of all Registry entries in 2010 to 12 % in 2011. Entries involving psychoactive drugs of abuse also increased twofold from 2010 to 2011 jumping 3 to 6 %, primarily due to increasing frequency of synthetic cannabinoid ("K2") related intoxications as 2011 progressed. The 2011 Registry included over 600 ADR's (10 % of Registry Cases) with 115 agents causing at least 2 ADR's. This is up from only 3 % of cases (116 total cases) in 2010. The ToxIC Case Registry continues to grow. At the end of 2011, over 10,000 cases had been entered into the Registry. As demonstrated by the trends identified in psychoactive bath salt and synthetic cannabinoid reports, the Registry is a valuable toxicosurveillance and research tool. The ToxIC Registry is a unique tool for identifying and characterizing confirmed cases of significant or potential toxicity or complexity to require bedside consultation by a medical toxicologist.

[Involvement of cross interaction between central cholinergic and histaminergic systems in the nucleus tractus solitarius in regulating carotid sinus baroreceptor reflex].

PubMed

Hu, Li-Xun; Zhang, Guo-Xing; Zhang, Yu-Ying; Zhao, Hong-Fen; Yu, Kang-Ying; Wang, Guo-Qing

2013-12-25

The carotid sinus baroreceptor reflex (CSR) is an important approach for regulating arterial blood pressure homeostasis instantaneously and physiologically. Activation of the central histaminergic or cholinergic systems results in CSR functional inhibitory resetting. However, it is unclear whether two systems at the nucleus tractus solitarius (NTS) level display cross interaction to regulate the CSR or not. In the present study, the left or right carotid sinus region was isolated from the systemic circulation in Sprague-Dawley rats (sinus nerve was reserved) anesthetized with pentobarbital sodium. Respective intubation was conducted into one side isolated carotid sinus and into the femoral artery for recording the intracarotid sinus pressure (ISP) and mean arterial pressure (MAP) simultaneously with pressure transducers connection in vivo. ISP was set at the level of 0 mmHg to eliminate the effect of initial internal pressure of the carotid sinus on the CSR function. To trigger CSR, the ISP was quickly elevated from 0 mmHg to 280 mmHg in a stepwise manner (40 mmHg) which was added at every step for over 4 s, and then ISP returned to 0 mmHg in similar steps. The original data of ISP and corresponding MAP were fitted to a modified logistic equation with five parameters to obtain the ISP-MAP, ISP-Gain relationship curves and the CSR characteristic parameters, which were statistically compared and analyzed separately. Under the precondition of no influence on the basic levels of the artery blood pressure, the effects and potential regulatory mechanism of preceding microinjection with different cholinoceptor antagonists, the selective cholinergic M1 receptor antagonist, i.e., pirenzepine (PRZ), the M2 receptor antagonist, i.e., methoctramine (MTR) or the N1 receptor antagonist, i.e., hexamethonium (HEX) into the NTS on the changes in function of CSR induced by intracerebroventricular injection (i.c.v.) of histamine (HA) in rats were observed. Meanwhile, the actions and possible modulatory mechanism of preceding microinjection with different histaminergic receptor antagonists, the selective histaminergic H1 receptor antagonist, i.e., chlorpheniramine (CHL) or the H2 receptor antagonist, i.e., cimetidine (CIM) into the NTS on the changes in function of CSR resulted from the i.c.v. cholinesterase inhibitor, physostigmine (PHY) were also examined in order to confirm and to analyze effects of cross interaction between central histaminergic and cholinergic systems on CSR. The main results obtained are as follows. (1) Standalone microinjection of different selective cholinergic receptor antagonists (PRZ, MTR or HEX) or different selective histaminergic receptor antagonists (CHL or CIM) into the NTS with each given dose had no effects on the CSR function and on the basic levels of the artery blood pressure, respectively (P > 0.05). (2) The pretreatment of PRZ or MTR into the NTS with each corresponding dose could attenuate CSR resetting resulted from i.c.v. HA in some degrees, which remarkably moved the posterior half range of ISP-MAP relationship curve downwards (P < 0.05), shifted the middle part of ISP-Gain relationship curve upwards (P < 0.05), and increased reflex parameters such as the MAP range and maximum gain (P < 0.05), but decreased parameters such as saturation pressure and intracarotid sinus pressure at maximum gain (P < 0.05). The catabatic effects of pretreatment with MTR into the NTS on CSR resetting induced by i.c.v. HA were more obvious than those with PRZ (P < 0.05), but pretreatment of HEX with given dose into the NTS had no effects on CSR resetting induced by i.c.v. HA (P > 0.05). (3) The effects of pretreatment of CHL or CIM into the NTS with each corresponding dose on CSR resetting made by i.c.v. PHY were similar to those of pretreatment of PRZ or MTR into the NTS on CSR resetting resulted from i.c.v. HA, and the decreasing effects of pretreatment with CHL into the NTS on CSR resetting induced by i.c.v. PHY were more remarkable than those with CIM (P < 0.05). These findings suggest that CSR resetting resulted from either HA or PHY into the lateral ventricle may partly involve the descending histaminergic or cholinergic pathway from the hypothalamus to NTS, which might evoke a cross activation of the cholinergic system in the NTS, via cholinergic M1 and M2 receptors mediation, especially the M2 receptors showing actions, or trigger another cross activation of the histaminergic system in the NTS, by histaminergic H1 and H2 receptors mediation, especially the H1 receptors displaying effects.