The Role of Serotonin in Memory: Interactions with Neurotransmitters and Downstream Signaling
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Severe Organophosphate Poisoning with Delayed Cholinergic Crisis, Intermediate Syndrome and Organophosphate Induced Delayed Polyneuropathy on Succession
Organophosphate Poisoning… Aklilu A 203 CASE REPORT SEVERE ORGANOPHOSPHATE POISONING WITH DELAYED CHOLINERGIC CRISIS, INTERMEDIATE SYNDROME AND ORGANOPHOSPHATE INDUCED DELAYED POLYNEUROPATHY ON SUCCESSION Aklilu Azazh ABSTRACT Organophosphate compounds are the organic derivatives of Phosphorous containing acids and their effect on neuromuscular junction and Autonomic Synapses is clinically important. After exposure these agents cause acute and sub acute manifestations depending on the type and severity of the agents like Acute Cholinergic Manifestations, Intermediate Syndrome with Nicotinic features and Delayed Central Nervous System Complications. The patient reported here had severe Organophosphate Poisoning with various rare complications on a succession. This is the first report of Organophosphates Poisoning complicated by Intermediate Syndrome and Organophosphate Induced Delayed Polyneuropathy in Ethiopia and it is reported to increase awareness of health care workers on these rare complications of a common problem. INTRODUCTION phosphorylated by the Phosphate end of Organophosphates; then the net result is Organophosphate compounds are the organic accumulation of excessive Acetyl Chlorine with derivatives of Phosphorous containing acids and resultant effect on Muscarinic, Nicotinic and their effect on Neuromuscular Junction and central nervous system (Figure 2). Autonomic synapses is clinically important. In the Neuromuscular Junction Acetylcholine is released Following classical OP poisoning, three well when a nerve impulse reaches -
Protocol for a Randomised Controlled Trial: Efficacy of Donepezil Against
BMJ Open: first published as 10.1136/bmjopen-2013-003533 on 25 September 2013. Downloaded from Open Access Protocol Protocol for a randomised controlled trial: efficacy of donepezil against psychosis in Parkinson’s disease (EDAP) Hideyuki Sawada, Tomoko Oeda To cite: Sawada H, Oeda T. ABSTRACT ARTICLE SUMMARY Protocol for a randomised Introduction: Psychosis, including hallucinations and controlled trial: efficacy of delusions, is one of the important non-motor problems donepezil against psychosis Strengths and limitations of this study in patients with Parkinson’s disease (PD) and is in Parkinson’s disease ▪ In previous randomised controlled trials for (EDAP). BMJ Open 2013;3: possibly associated with cholinergic neuronal psychosis the efficacy was investigated in patients e003533. doi:10.1136/ degeneration. The EDAP (Efficacy of Donepezil against who presented with psychosis and the primary bmjopen-2013-003533 Psychosis in PD) study will evaluate the efficacy of endpoint was improvement of psychotic symp- donepezil, a brain acetylcholine esterase inhibitor, for toms. By comparison, this study is designed to prevention of psychosis in PD. ▸ Prepublication history for evaluate the prophylactic effect in patients this paper is available online. Methods and analysis: Psychosis is assessed every without current psychosis. Because psychosis To view these files please 4 weeks using the Parkinson Psychosis Questionnaire may be overlooked and underestimated it is visit the journal online (PPQ) and patients with PD whose PPQ-B score assessed using a questionnaire, Parkinson (http://dx.doi.org/10.1136/ (hallucinations) and PPQ-C score (delusions) have Psychosis Questionnaire (PPQ) every 4 weeks. bmjopen-2013-003533). been zero for 8 weeks before enrolment are ▪ The strength of this study is its prospective randomised to two arms: patients receiving donepezil design using the preset definition of psychosis Received 3 July 2013 hydrochloride or patients receiving placebo. -
Drug Class Review Ophthalmic Cholinergic Agonists
Drug Class Review Ophthalmic Cholinergic Agonists 52:40.20 Miotics Acetylcholine (Miochol-E) Carbachol (Isopto Carbachol; Miostat) Pilocarpine (Isopto Carpine; Pilopine HS) Final Report November 2015 Review prepared by: Melissa Archer, PharmD, Clinical Pharmacist Carin Steinvoort, PharmD, Clinical Pharmacist Gary Oderda, PharmD, MPH, Professor University of Utah College of Pharmacy Copyright © 2015 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved. Table of Contents Executive Summary ......................................................................................................................... 3 Introduction .................................................................................................................................... 4 Table 1. Glaucoma Therapies ................................................................................................. 5 Table 2. Summary of Agents .................................................................................................. 6 Disease Overview ........................................................................................................................ 8 Table 3. Summary of Current Glaucoma Clinical Practice Guidelines ................................... 9 Pharmacology ............................................................................................................................... 10 Methods ....................................................................................................................................... -
Neuronal Nicotinic Receptors
NEURONAL NICOTINIC RECEPTORS Dr Christopher G V Sharples and preparations lend themselves to physiological and pharmacological investigations, and there followed a Professor Susan Wonnacott period of intense study of the properties of nAChR- mediating transmission at these sites. nAChRs at the Department of Biology and Biochemistry, muscle endplate and in sympathetic ganglia could be University of Bath, Bath BA2 7AY, UK distinguished by their respective preferences for C10 and C6 polymethylene bistrimethylammonium Susan Wonnacott is Professor of compounds, notably decamethonium and Neuroscience and Christopher Sharples is a hexamethonium,5 providing the first hint of diversity post-doctoral research officer within the among nAChRs. Department of Biology and Biochemistry at Biochemical approaches to elucidate the structure the University of Bath. Their research and function of the nAChR protein in the 1970’s were focuses on understanding the molecular and facilitated by the abundance of nicotinic synapses cellular events underlying the effects of akin to the muscle endplate, in electric organs of the acute and chronic nicotinic receptor electric ray,Torpedo , and eel, Electrophorus . High stimulation. This is with the goal of affinity snakea -toxins, principallyaa -bungarotoxin ( - Bgt), enabled the nAChR protein to be purified, and elucidating the structure, function and subsequently resolved into 4 different subunits regulation of neuronal nicotinic receptors. designateda ,bg , and d .6 An additional subunit, e , was subsequently identified in adult muscle. In the early 1980’s, these subunits were cloned and sequenced, The nicotinic acetylcholine receptor (nAChR) arguably and the era of the molecular analysis of the nAChR has the longest history of experimental study of any commenced. -
Monoamine Oxidase Inhibitors: Promising Therapeutic Agents for Alzheimer's Disease (Review)
MOLECULAR MEDICINE REPORTS 9: 1533-1541, 2014 Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer's disease (Review) ZHIYOU CAI Department of Neurology, The Lu'an Affiliated Hospital of Anhui Medical University, Lu'an People's Hospital, Lu'an, Anhui 237005, P.R. China Received July 2, 2013; Accepted February 10, 2014 DOI: 10.3892/mmr.2014.2040 Abstract. Activated monoamine oxidase (MAO) has a critical 6. MAO activation contributes to cognitive impairment in role in the pathogenesis of Alzheimer's disease (AD), including patients with AD the formation of amyloid plaques from amyloid β peptide (Aβ) 7. Activated MAO contributes to the formation of amyloid production and accumulation, formation of neurofibrillary plaques tangles, and cognitive impairment via the destruction of cholin- 8. Is activated MAO associated with the formation of ergic neurons and disorder of the cholinergic system. Several neurofibrillary tangles? studies have indicated that MAO inhibitors improve cognitive 9. Evidence for the neuroprotective effect of MAO inhibitors deficits and reverse Aβ pathology by modulating proteolytic in AD cleavage of amyloid precursor protein and decreasing Aβ 10. Conclusions and outlook protein fragments. Thus, MAO inhibitors may be considered as promising therapeutic agents for AD. 1. Introduction Monoamine oxidase (MAO) catalyzes the oxidative deamina- Contents tion of biogenic and xenobiotic amines and has an important role in the metabolism of neuroactive and vasoactive amines in 1. Introduction the central nervous system (CNS) and peripheral tissues. The 2. Monoamine oxidase (MAO) enzyme preferentially degrades benzylamine and phenylethyl- 3. Involvement of MAO in neurodegeneration amine and targets a wide variety of specific neurotransmitters 4. -
Cholinergic Regulation of the Suprachiasmatic Nucleus Circadian Rhythm Via a Muscarinic Mechanism at Night
The Journal of Neuroscience, January 15, 1996, 16(2):744-751 Cholinergic Regulation of the Suprachiasmatic Nucleus Circadian Rhythm via a Muscarinic Mechanism at Night Chen Liul and Martha U. Gillette’,2,3 1Neuroscience Program, and Departments of 2Cell and Structural Biology and 3Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 6 180 I In mammals, the suprachiasmatic nucleus (SCN) is responsible for agonists, muscarine and McN-A-343 (Ml-selective), but not by the generation of most circadian rhythms and for their entrainment nicotine. Furthermore, the effect of carbachol was blocked by the to environmental cues. Carbachol, an agonist of acetylcholine mAChR antagonist atropine (0.1 PM), not by two nicotinic antag- (ACh), has been shown to shift the phase of circadian rhythms in onists, dihydro-6-erythroidine (10 PM) and d-tubocurarine (10 PM). rodents when injected intracerebroventricularly. However, the site The Ml -selective mAChR antagonist pirenzepine completely and receptor type mediating this action have been unknown. In blocked the carbachol effect at 1 PM, whereas an M3-selective the present experiments, we used the hypothalamic brain-slice antagonist, 4,2-(4,4’-diacetoxydiphenylmethyl)pyridine, partially technique to study the regulation of the SCN circadian rhythm of blocked the effect at the same concentration. These results dem- neuronal firing rate by cholinergic agonists and to identify the onstrate that carbachol acts directly on the SCN to reset the receptor subtypes involved. We found that the phase of the os- phase of its firing rhythm during the subjective night via an Ml -like cillation in SCN neuronal activity was reset by a 5 min treatment mAChR. -
Ketamine Dual Therapy Stops Cholinergic Status
FULL-LENGTH ORIGINAL RESEARCH Midazolam–ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits *†Jerome Niquet, †Roger Baldwin, †Keith Norman, †Lucie Suchomelova, ‡Lucille Lumley, and *†§Claude G. Wasterlain Epilepsia, **(*):1–10, 2016 doi: 10.1111/epi.13480 SUMMARY Objective: Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic c-aminobutyric acid A (GABAA) receptors and externalization of N-methyl-D-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug com- bination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. Methods: A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. Results: Midazolam–ketamine dual therapy was more efficient than double-dose Jerome Niquet is an midazolam or ketamine monotherapy or than valproate–midazolam or valproate– associate researcher ketamine dual therapy in reducing several parameters of SE severity, suggesting a at the Department of synergistic mechanism. In addition, midazolam–ketamine dual therapy reduced Neurology, David SE-induced acute neuronal injury, epileptogenesis, and MWM deficits. Geffen School of Significance: This study showed that a treatment aimed at correcting maladaptive Medicine at UCLA. -
Alzheimer Dementia: Starting, Stopping Drug Therapy
REVIEW CME CREDIT LUKE D. KIM, MD, FACP, CMD RONAN M. FACTORA, MD, FACP, AGSF Assistant Professor of Medicine, Cleveland Clinic Lerner Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, College of Medicine of Case Western Reserve University, Cleveland, OH; Center for Geriatric Medicine, Medicine Cleveland, OH; Center for Geriatric Medicine, Medicine Institute, Cleveland Clinic Institute, Cleveland Clinic Alzheimer dementia: Starting, stopping drug therapy ABSTRACT lzheimer disease is the most common A form of dementia. In 2016, an estimated Alzheimer disease is the most common type of dementia. 5.2 million Americans age 65 and older had Two classes of cognition-enhancing drugs are approved Alzheimer disease. The prevalence is project- to treat the symptoms, and both have provided modest ed to increase to 13.8 million by 2050, includ- benefi t in clinical trials. Psychotropic drugs are sometimes ing 7 million people age 85 and older.1 used off-label to treat behavioral symptoms of Alzheimer Although no cure for dementia exists, sev- disease. All these medications should be continuously eral cognition-enhancing drugs have been ap- evaluated for clinical effi cacy and, when appropriate, proved by the US Food and Drug Administra- discontinued if the primary benefi t—preservation of cog- tion (FDA) to treat the symptoms of Alzheimer nitive and functional status and a reduction in behaviors dementia. The purpose of these drugs is to associated with dementia—is no longer being achieved. stabilize cognitive and functional status, with a secondary benefi t of potentially reducing be- KEY POINTS havioral problems associated with dementia. -
Drugs Affecting the Autonomic Nervous System-3 Cholinergic Antagonists Assistant Prof
Drugs Affecting the Autonomic Nervous System-3 Cholinergic Antagonists Assistant Prof. Dr. Najlaa Saadi PhD Pharmacology Faculty of Pharmacy University of Philadelphia The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) Bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these agents selectively block muscarinic synapses of the parasympathetic nerves Cholinergic antagonist classified into: Antimuscarinic Agents: • M1 Selective. • Non selective. Antinicotinic Agents: • Ganglionic Blocking Agents. • Neuromuscular Blocking Agents. Antimuscarinic Agents Tertiary amine (Alkaloid esters of tropic acid) • Atropine: (prototype) • Hemoatropine: • Scopolamine. Quaternary amine (Semi synthetic & synthetic) Produce more peripheral effects with decrease CNS effect. • Propantheline • Ipratropium • Clidinium bromide. Sites of Actions of Cholinergic Antagonists Antimuscarinic Agents Tertiary amine Atropine A tertiary amine belladonna alkaloid Acts both centrally and peripherally It has a high affinity for muscarinic receptors, binds competitively & reversiblely,preventing Ach from binding to that site. Block muscarinic receptors causing inhibition of all muscarinic functions. Block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands. Have little or no action at skeletal neuromuscular junctions or autonomic ganglia (because they do not block nicotinic receptors). -
Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists As Potential Disease-Modifying Agents for Alzheimer’S Disease
Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Cholinergic Treatments with Emphasis on M1 Muscarinic Agonists as Potential Disease-Modifying Agents for Alzheimer’s Disease Abraham Fisher Israel Institute for Biological Research, P. O. Box 19, Ness-Ziona 74100, Israel Summary: The only prescribed drugs for treatment of Alzhei- formation of -amyloid plaques, and tangles containing hyper- mer’s disease (AD) are acetylcholinesterase inhibitors (e.g., phosphorylated tau proteins) are apparently linked. Such link- donepezil, rivastigmine, galantamine, and tacrine) and meman- ages may have therapeutic implications, and this review is an tine, an NMDA antagonist. These drugs ameliorate mainly the attempt to analyze these versus the advantages and drawbacks symptoms of AD, such as cognitive impairments, rather than of some cholinergic compounds, such as acetylcholinesterase halting or preventing the causal neuropathology. There is cur- inhibitors, M1 muscarinic agonists, M2 antagonists, and nico- rently no cure for AD and there is no way to stop its progres- tinic agonists. Among the reviewed treatments, M1 selective sion, yet there are numerous therapeutic approaches directed agonists emerge, in particular, as potential disease modifiers. against various pathological hallmarks of AD that are exten- Key Words: Alzheimer’s, cholinergic, -amyloid, tau, acetyl- sively being pursued. In this context, the three major hallmark cholinesterase inhibitors, M1 muscarinic, nicotinic, agonists, characteristics of AD (i.e., the CNS cholinergic hypofunction, M2 muscarinic antagonists. INTRODUCTION (␣-APPs) that is neurotrophic and neuroprotective. In an alternate pathway, -secretase (BACE1) cleaves APP Alzheimer’s disease (AD) is a progressive, neurode- releasing a large secreted derivative sAPP andaC- generative disease that is a major health problem in terminal fragment C99 that can be further cleaved by modern societies. -
Basal Forebrain Glutamatergic Modulation of Cortical Acetylcholine Release
SYNAPSE 39:201–212 (2001) Basal Forebrain Glutamatergic Modulation of Cortical Acetylcholine Release JIM FADEL, MARTIN SARTER, AND JOHN P. BRUNO* Departments of Psychology and Neuroscience, The Ohio State University, Columbus, Ohio KEY WORDS acetylcholine; basal forebrain; cortex; microdialysis; glutamate recep- tors; kainate; NMDA ABSTRACT The mediation of cortical ACh release by basal forebrain glutamate receptors was studied in awake rats fitted with microdialysis probes in medial prefrontal cortex and ipsilateral basal forebrain. Repeated presentation of a stimulus consisting of exposure to darkness with the opportunity to consume a sweetened cereal resulted in a transient increase in cortical ACh efflux. This stimulated release was dependent on basal forebrain glutamate receptor activity as intrabasalis perfusion with the ionotropic glutamate receptor antagonist kynurenate (1.0 mM) markedly attenuated darkness/ cereal-induced ACh release. Activation of AMPA/kainate receptors by intrabasalis per- fusion of kainate (100 M) was sufficient to increase cortical ACh efflux even under basal (nonstimulated) conditions. This effect of kainate was blocked by coperfusion with the antagonist DNQX (0.1–5.0 mM). Stimulation of NMDA receptors with intrabasalis perfusion of NMDA (50 or 200 M) did not increase basal cortical ACh efflux. However, perfusion of NMDA in rats following exposure to the darkness/cereal stimulus resulted in a potentiation of both the magnitude and duration of stimulated cortical ACh efflux. Moreover, intrabasalis perfusion of the higher dose of NMDA resulted in a rapid increase in cortical ACh efflux even before presentation of the darkness/cereal stimulus, suggesting an anticipatory change in the excitability of basal forebrain cholinergic neurons. These data demonstrate that basal forebrain glutamate receptors contribute to the stimulation of cortical ACh efflux in response to behavioral stimuli. -
Treating Dementia with Cholinesterase Inhibitors Patient Information - Older Persons Mental Health
Treating Dementia with Cholinesterase Inhibitors Patient information - Older Persons Mental Health www.cdhb.health.nz/patientinfo Dementia is a progressive disease of the brain in which brain cells die and are not replaced. It results in impaired memory, thinking and behaviour. In recent years a number of medications for dementia have become available in New Zealand, includ- ing cholinesterase inhibitors, which are discussed below. For more information, please contact your GP or specialist. Other useful sources of information are Alzhei- mer’s Canterbury (314 Worcester St, Christchurch, phone (03) 379 2590) and the website www.alzheimers.org.nz click on “your Alzheimer’s organisation” to take you to Canterbury. Cholinesterase Cholinesterase Treating Dementia with with Dementia Treating Inhibitors Older Older Persons Mental Health How do cholinesterase inhibitors work? Cholinesterase inhibitors are designed to enhance memory and other brain functions by influencing chemical activity in the brain. Acetylcholine is a chemical messenger in the brain that is thought to be important for the function of brain cells involved in memory, thought and judgement. Acetylcholine is released by one brain cell to transmit a message to another. Once a message is received, various enzymes, including some called cholinesterases, break down the chemical messenger for reuse. In the brain affected by dementia, the cells that produce acetylcholine are damaged or destroyed, resulting in lower levels of the chemical messenger. A cholinesterase inhibitor is designed to reduce the activity of the cholinesterases, thereby slowing down the breakdown of acetylcholine. By maintaining levels of acetylcholine, the drug may help compensate for the loss of functioning brain cells.