Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study of the drugs effective in the treatment of cognitive deficits and memory loss associated with senile dementia of the Alzheimer's type--tacrine and amiridin, acetylcholinesterase inhibitor physostigmine and nootrop piracetam on uptake of 3H-serotonin (3H-5-HT), 3H-adrenaline (3H-AD), 3H-noradrenaline (3H-HA), 2H-dopamine (3H-DA), 3H-gamma-aminobutyric acid (3H-GABA), 3H-glutamic acid (3H-GLU), 3H-aspartic acid (3H-ASP) and 3H-glycine (3H-GLI) showed that tacrine and amiridin (5 x 10(-5) M) statistically significantly (P less than 0.05) inhibited the uptake of 3H-DA and 3H-5-HT. Physostigmine at concentration 5 x 10(-4) M statistically significantly (P less than 0.05) inhibited uptake of 3H-5-HT only. Piracetam at concentration range 1-5 x 10(-3) M had no effect on uptake of all investigated neurotransmitters. The above finding suggest that the uptake of neurotransmitter in nerve terminals is not the main target of amiridin and tacrine.
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PMID:[Effects of amiridin and tacrine, drugs effective in Alzheimer's disease, on synaptosomal uptake of neuromediators]. 135 7

Using a three-panel runway task, the influence of dorsal hippocampal lesions on working and reference memory in rats was investigated. Despite 20 postoperative training sessions, rats with hippocampal lesions were unable to perform the working memory task. In the acquisition process of the reference memory task, however, there was no significant difference between hippocampal- and sham-lesioned rats. On the other hand, rats trained preoperatively with a working memory procedure, and then subjected to hippocampal lesions, showed more errors (pushes made on the two incorrect panels of the three panel-gates located at four choice points) than did sham-lesioned rats. The increase in working errors induced by hippocampal lesions was not reduced during 10 subsequent re-training sessions. Hippocampal lesions had no effect on retention of the reference memory performance. The increase in working errors in hippocampal-lesioned rats was significantly reduced by treatment with the cholinesterase inhibitor physostigmine at 0.1 mg/kg and the cholinergic activating drug minaprine at 10 mg/kg. These findings suggest that lesions of the dorsal hippocampus selectively impair the ability to carry out the working memory task whether rats are trained preoperatively or postoperatively, and that the working memory loss in hippocampal-lesioned rats is mediated by lowering of the cholinergic function.
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PMID:Working and reference memory in rats in the three-panel runway task following dorsal hippocampal lesions. 150 23

The pathophysiology, symptomatology, and treatment of memory loss in patients with Alzheimer's disease are described. Alzheimer's disease is characterized by cerebral cortical atrophy, neuronal loss, neurofibrillary tangles, and neuritic plaques. The primary neuropharmacologic defect involves reduced activity of the enzyme choline acetyltransferase, causing reduced synthesis of acetylcholine (ACh). Other neurotransmitters known to be compromised in patients with Alzheimer's disease include norepinephrine, serotonin, dopamine, and somatostatin. Initially components of short-term memory and immediate recall are lost. Eventually, memory loss is so severe that patients lose the ability to care for themselves. A definite diagnosis of Alzheimer's disease can be made only at autopsy. Three pharmacologic approaches to enhancing cholinergic function include increasing ACh production by increasing the availability of ACh precursors (lecithin, choline); inhibiting ACh degradation by inhibiting acetylcholinesterase (physostigmine, tacrine hydrochloride); and directly stimulating cholinergic receptors by using cholinomimetic agents (arecoline, RS-86). However, results of studies involving these agents are conflicting: no consistent benefit has been shown in patients with Alzheimer's disease. Although therapy with tacrine hydrochloride has been beneficial in some patients, it has not been effective in all cases and has the potential to cause serious adverse effects. Despite the research in patients with Alzheimer's disease, no agent has yet been found that produces consistent improvement in the memory loss associated with this disease.
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PMID:Alternatives in the treatment of memory loss in patients with Alzheimer's disease. 206 22

Acute peripheral administration of physostigmine inhibits cortical acetylcholinesterase (AChE) for about 1 hr in the rat and improves performance on learning and memory paradigms after excitotoxic lesions of the nucleus basalis magnocellularis (NBM) in rats. This study examined the effects of continuous systemic infusion of physostigmine using osmotic minipumps. One week of continuous physostigmine infusion in normal animals inhibited cortical AChE activity in a dose-dependent manner. Doses causing near maximal (0.06 mg/kg/hr) and ED50 (0.0075 mg/kg/hr) inhibition of cortical AChE activity were used to determine the effects of continuous physostigmine administration on spatial learning in the water maze in rats with bilateral ibotenic acid lesions of the NBM. Physostigmine had no effect on the acquisition of the maze task but prevented the retention deficit measured in untreated NBM-lesioned rats. Physostigmine treatment also improved the search strategy during the spatial probe trial compared to the untreated NBM-lesioned rats. The two doses of physostigmine examined did not produce differential responses on behavioral measures. Although NBM lesions significantly depleted cortical AChE activity, physostigmine treatment reduced the activity further in a dose-dependent manner. Whereas neither the lesion nor the low dose of physostigmine altered cortical receptor binding, the higher dose of physostigmine significantly down-regulated cortical muscarinic receptor binding by 28%. These data demonstrate that enhancement of acetylcholine neurotransmission can improve memory loss and spatial strategy associated with excitotoxic NBM lesions.
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PMID:Continuous physostigmine infusion in rats with excitotoxic lesions of the nucleus basalis magnocellularis: effects on performance in the water maze task and cortical cholinergic markers. 281 Jan 14

Carbaryl, a widely used insecticide, is reputed to have a wide safety margin. It can induce acute cholinesterase poisoning, which is rapidly reversible on discontinuation of exposure. Long-term sequelae from long-term exposure have not previously been described in humans. This report describes the experience of a 75-year-old man who had long-term excessive exposure to carbaryl and in whom a debilitating syndrome, including headaches, memory loss, proximal muscle weakness, muscle fasciculation, muscle cramps, and anorexia with marked weight loss, developed. At the time of diagnosis, serum pseudocholinesterase levels were low, and his major symptoms resolved on termination of exposure. Late clinical features were sleep apnea and progressive development of a peripheral neuropathy. The difficulty in diagnosing the cause of a group of relatively nonspecific symptoms raises the question of whether chronic carbaryl neurotoxicity might be occurring more frequently than previously suspected.
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PMID:Subacute neurotoxicity following long-term exposure to carbaryl. 308 76

A correlation was found among the degree of memory loss, intellectual impairment, the quantity of senile plaques, and a decrease in choline acetyltransferase and acetylcholinesterase activity in patients affected by senile dementia of the Alzheimer type. In this study, patients were subjected to a series of computerized electroencephalographic (EEG) recordings and neuropsychological evaluations after acute administration of the following drugs: placebo; the cholinergic drugs physostigmine, pyridostigmine bromide, and edrophonium chloride; and the anticholinergic drugs scopolamine and orphenadrine. The results obtained show that the acute administration of some cholinergic drugs improved memory and attention performances, whereas the anticholinergic drugs induced opposite effects. The cholinergic drugs exhibited a tendency to shift the EEG spectrum analysis into more normal patterns compatible with the patient's age. This study supports the view that the cholinergic system plays an important role in memory and attention disturbances found in senile dementia of the Alzheimer type.
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PMID:Effect of cholinergic and anticholinergic drugs on short-term memory in Alzheimer's dementia: a neuropsychological and computerized electroencephalographic study. 666 30

A chronic diet of ethanol has detrimental effects on the cholinergic system in adult humans and rats. This study examined the effects of chronic exposure to dietary ethanol on the anatomical organization of true acetylcholinesterase (AChE) active elements in rat cerebral cortex. We focused on the somatosensory cortex because of its highly organized chemical and cellular structure. Following 42 days of exposure to an ethanol diet (6.7% v/v), there were marked changes in the cortical plexus of AChE-positive fibers. The AChE-positive plexus in ethanol-treated rats was reduced in all cortical layers, in comparison to age-matched pair-fed control and chow-fed rats. The most marked reduction was evident in layers II/III, IV, and VIa. Moreover, the density of AChE-positive cell bodies was significantly reduced in the cortices of ethanol-fed rats, particularly in the deep laminae. These alterations in the chemoarchitecture of somatosensory cortex occurred in the absence of changes in the cytoarchitectonic organization of neocortex. There was no detectable ethanol-induced change in the density of Cresyl violet-stained neurons either in the horizontal limb of the diagonal band of Broca or in the nucleus basalis. The density of AChE-positive neurons in the nucleus basalis, however, was significantly lower in ethanol-fed rats than in controls. Thus, it appears that a mere 6 weeks of ethanol exposure is sufficient to alter the cholinergic innervation of the cerebral cortex. These cortical alterations occur despite the lack of an ethanol-induced death of neurons in the basal forebrain. Such changes may contribute to the memory loss associated with alcohol dementia.
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PMID:Effects of chronic ethanol administration on acetylcholinesterase activity in the somatosensory cortex and basal forebrain of the rat. 829 90

Alzheimer's disease is a progressive neurodegenerative disorder primarily manifesting as a loss of memory. Senile plaques and neurofibrillary tangles are the major histopathological alteration in the brain of Alzheimer's disease patients. A considerable deficiency of cholinergic neurons is a consistent finding in Alzheimer's disease. Therefore, many therapeutic strategies to augment cerebral concentration of acetylcholine such as cholinergic precursors, cholinergic receptor agonists, cholinesterase inhibitors and acetylcholine release modulators have been evaluated in Alzheimer's disease. Although cholinesterase inhibitors such as tacrine and galanthamine offer modest clinical benefits, other cholinergic agents have proved to be of limited therapeutic value. Efforts to enhance monoaminergic neurotransmission have also been largely disappointing. Therefore, emphasis is not being put on the use of combination of two class of drugs. Moreover, use of therapeutic agents based on the putative pathogenic etiology of the disease such as excitotoxicity, amyloidosis, aluminium accumulation, inflammatory mechanisms and free radical production is being evaluated. Desferrioxamine, non-steroidal anti-inflammatory drugs, prednisone, dapsone, vitamin E and idebenone are some such agents that are currently under investigation for the preventive or palliative effect in Alzheimer's disease. Neurotrophic factors such as nerve growth factor, brain derived neurotrophic factor and epidermal growth factor have shown promising results in animal studies. However, novel methods for delivering these molecules into the brain required to be developed before launching their clinical trials in man.
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PMID:Pharmacological basis of drug therapy of Alzheimer's disease. 956 41

Alzheimer's disease is, in part, characterised by the loss of neurones in the basal forebrain cholinergic cells that project to the cerebral cortex and hippocampus. These impairments have correlated with the memory loss noted in dementia of the Alzheimer's type. This 'cholinergic hypothesis' has led to the rational design of drugs to enhance or stimulate acetylcholine-mediated neurotransmission. Early acetylcholinesterase inhibitors, such as tacrine and physostigmine, are poorly tolerated and have a short duration of action. Rivastigmine is a centrally-selective acetylcholinesterase inhibitor with a relatively long duration of action and is a 'pseudo-irreversible' cholinesterase inhibitor due to slow dissociation of a carbamoyl derivative from the esteratic site of acetylcholinesterase. Preclinical studies confirmed the central selectivity of the drug and its distribution into the cerebrospinal fluid (CSF). Early studies demonstrated that rivastigmine improved cognition and was relatively well-tolerated at moderate doses. Clinical investigations of rivastigmine administered at doses of 6 - 12 mg/day significantly improved cognition, as measured by the ADAS-Cog score, and activities of daily living, as measured by the Progressive Deterioration Scale. Significant global improvements were also noted as measured by the Clinician's Interview Based Impression of Change that required the use of caregiver information. The most frequent adverse effects noted in clinical trials were consistent with peripheral cholinergic stimulation and included nausea, vomiting, abdominal pain, dizziness and diarrhoea. These effects were dose-related and minimised by slow dose-escalation upon initiation of therapy. Rivastigmine undergoes minimal metabolism by the cytochrome P450 system. As a result, it has few drug interactions. The drug is currently marketed widely in over 60 countries worldwide. In the United States, the drug received 'approvable' status subsequent to the NDA filing, and should be available later this year.
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PMID:Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. 1113 19

In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmacology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders.
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PMID:A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials. 1211 73


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