Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

After only 1 day of treatment with a thiamine-deficient diet and pyrithiamine, a centrally and peripherally acting thiamine antagonist, 37.5% of rats performed poorly on a standardized string test. By day 12, 89.6% of the pyrithiamine-treated rats, but only 8.1% of the pair-fed controls, had decreased string test scores. Scores for rats treated with a thiamine-deficient diet and oxythiamine, a peripherally acting thiamine antagonist, did not decrease even on the day before death. The acetylcholinesterase inhibitor physostigmine improved the low string test scores in 69.2% of trials with the pyrithiamine-treated rats, whereas neostigmine, which acts peripherally, had no effect. The effect of physostigmine was inhibited by the muscarinic blocker atropine, but not by methatropine, its peripherally acting analog. Arecoline, a direct muscarinic agonist, was as effective as physostigmine or thiamine in restoring string test performance. Nicotine had no effect and the nicotinic blocker mecamylamine did not alter the effect of physostigmine. Incorporation of [2H4]choline and [U-14C]glucose into acetylcholine was decreased by 32 and 48%, respectively, relative to pair-fed controls after 12 days of pyrithiamine treatment. Acetylcholine levels were unchanged. Thiamine deficiency induces an early functionally significant central muscarinic cholinergic lesion.
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PMID:Impairment of behavior and acetylcholine metabolism in thiamine deficiency. 722 89

We studied at the biochemical, morphological, and behavioral levels the effect of chronic ethanol consumption, associated or not with a mild thiamine deficiency episode. We found that (i) thiamine deficiency induced a significant decrease of the acetylcholinesterase (AChE) activity both in cortex and hippocampus; (ii) chronic ethanol treatment has no effect on cortical AChE activity, but induced a significant decrease of hippocampal enzyme activity; (iii) the reduction in cortical and hippocampal AChE activity induced by chronic ethanol treatment associated with a 1-week thiamine deficiency was also significant and was greater than that induced by ethanol alone. Furthermore, either chronic ethanol or thiamine deficiency induced a significant decrease in the release of acetylcholine (ACh) in the stimulated condition using high potassium concentration; and when both treatments were associated the decrease was even greater. In the unstimulated condition, the reduction in the release of ACh was greater for ethanol treatment than for thiamine deficiency. Open-field tests showed that only in the "sniffing" category were there significant differences among the experimental groups. No morphological change was detected by optical microscopy, suggesting that the injury process was in its initial stages in which only functional and behavioral changes are displayed. In addition, our biochemical results indicate that cortical cholinergic susceptibilities to ethanol and thiamine deficiency are significantly different.
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PMID:The contribution of mild thiamine deficiency and ethanol consumption to central cholinergic parameter dysfunction and rats' open-field performance impairment. 1170 Nov 92

Wernicke-Korsakoff's disease (WKD) is cognitively an amnestic state resulting from strategic lesions in the limbic system subserving the episodic memory network and resulting from thiamine deficiency. Neurochemical deficits have been implicated in the pathophysiology of amnesia based on the pathologic observations that various brainstem and basal forebrain nuclei are also affected. Previous treatment attempts with serotoninergic, noradrenergic, and cholinergic drugs have given controversial results. The objective of this study was to assess the effects of a cholinesterase inhibitor, donepezil, on memory, attention, and executive functions in patients with nonalcoholic WKD. Seven patients who developed WKD after a hunger strike were included in this single, blind, placebo-controlled, one-way, crossover study. The patients were administered donepezil during the first 30 days, and were administered placebo during the following 30 days. Neuropsychological tests to evaluate verbal and visual memory, and attention and executive function were performed on days 0, 31, and 61. All patients completed both phases of the study. There were no statistically significant differences between the three evaluations, except for a difference between active treatment and the placebo phase during recall of the Rey-Osterrieth complex figure, which was in favor of the placebo phase. There were no significant changes in favor of the active treatment. Cholinergic treatment with the cholinesterase inhibitor donepezil does not seem to provide marked beneficial effects in patients with WKD in this small, descriptive study. This may be because pathways mediating channel and state-dependent functions are impaired in this disease, and enhancement of state-dependent cholinergic transmission may not be sufficient. Subtle benefits, however, cannot be excluded because of the small sample size and the relatively short duration of the treatment.
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PMID:Therapeutic effects of an acetylcholinesterase inhibitor (donepezil) on memory in Wernicke-Korsakoff's disease. 1185 91

This is a factorial (2 x 2 x 2) spatial memory and cholinergic parameters study in which the factors are chronic ethanol, thiamine deficiency and naivety in Morris water maze task. Both learning and retention of the spatial version of the water maze were assessed. To assess retrograde retention of spatial information, half of the rats were pre-trained on the maze before the treatment manipulations of pyrithiamine (PT)-induced thiamine deficiency and post-tested after treatment (pre-trained group). The other half of the animals was only trained after treatment to assess anterograde amnesia (post-trained group). Thiamine deficiency, associated to chronic ethanol treatment, had a significant deleterious effect on spatial memory performance of post-trained animals. The biochemical data revealed that chronic ethanol treatment reduced acetylcholinesterase (AChE) activity in the hippocampus while leaving the neocortex unchanged, whereas thiamine deficiency reduced both cortical and hippocampal AChE activity. Regarding basal and stimulated cortical acetylcholine (ACh) release, both chronic ethanol and thiamine deficiency treatments had significant main effects. Significant correlations were found between both cortical and hippocampal AChE activity and behaviour parameters for pre-trained but not for post-trained animals. Also for ACh release, the correlation found was significant only for pre-trained animals. These biochemical parameters were decreased by thiamine deficiency and chronic ethanol treatment, both in pre-trained and post-trained animals. But the correlation with the behavioural parameters was observed only for pre-trained animals, that is, those that were retrained and assessed for retrograde retention.
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PMID:Cholinergic parameters and the retrieval of learned and re-learned spatial information: a study using a model of Wernicke-Korsakoff Syndrome. 1592 63

Pyrithiamine-induced thiamine deficiency (PTD) was used to produce a rodent model of Wernicke-Korsakoff syndrome that results in acute neurological disturbances, thalamic lesions, and learning and memory impairments. There is also cholinergic septohippocampal dysfunction in the PTD model. Systemic (Experiment 1) and intrahippocampal (Experiment 2) injections of the acetylcholinesterase inhibitor physostigmine were administered to determine if increasing acetylcholine levels would eliminate the behavioral impairment produced by PTD. Prior to spontaneous alternation testing, rats received injections of either physostigmine (systemic=0.075 mg/kg; intrahippocampal=20, 40 ng/muL) or saline. In Experiment 2, intrahippocampal injections of physostigmine significantly enhanced alternation rates in the PTD-treated rats. In addition, although intrahippocampal infusions of 40 ng of physostigmine increased the available amount of ACh in both pair-fed (PF) and PTD rats, it did so to a greater extent in PF rats. The increase in ACh levels induced by the direct hippocampal application of physostigmine in the PTD model likely increased activation of the extended limbic system, which was dysfunctional, and therefore led to recovery of function on the spontaneous alternation task. In contrast, the lack of behavioral improvement by intrahippocampal physostigmine infusion in the PF rats, despite a greater rise in hippocampal ACh levels, supports the theory that there is an optimal range of cholinergic tone for optimal behavioral and hippocampal function.
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PMID:Increasing hippocampal acetylcholine levels enhance behavioral performance in an animal model of diencephalic amnesia. 1870 97

Several lines of evidence suggest that acetylcholinesterase inhibitors (AChE) have their cognitive enhancing effects by stimulating cholinergic receptors within the medial septum. However, intraseptal administration of cholinergic enhancing drugs produce mixed results that appear to depend on both the integrity of the medial septum as well as task demands. Three experiments were conducted to determine the relationship between increased cholinergic activity within the medial septum and hippocampus and behavioral recovery in a model of diencephalic amnesia produced by pyrithiamine-induced thiamine deficiency (PTD). In Experiment 1, systemic tacrine (0.0, 0.75, 1.5mg/kg) was administered to PTD and pair-fed (PF) rats prior to a spontaneous alternation task. Without tacrine, PF rats alternated at a higher rate than PTD rats. Both doses of tacrine increased alternation in PTD rats to within the range of PF rats. In Experiment 2, three doses of intraseptal tacrine (2.5, 5.0, 12.5microg) were administered to PTD and PF rats and changes in hippocampal acetylcholine efflux were assessed. Both the 5.0 and 12.5microg doses significantly increased hippocampal acetylcholine levels, but the change was greater in the PTD rats. In Experiment 3, despite the fact that both intraseptal doses of tacrine (5.0, 12.5microg) increased hippocampal acetylcholine levels, only 5.0microg significantly improved alternation scores in PTD rats. Thus, when there is basal forebrain cholinergic cell loss in conjunction with diencephalic pathology, the therapeutic range of AChE-I in the medial septum and the effective doses do not directly map onto changes in acetylcholine efflux in the hippocampus.
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PMID:Differential effects of systemic and intraseptal administration of the acetylcholinesterase inhibitor tacrine on the recovery of spatial behavior in an animal model of diencephalic amnesia. 2000

Nutritional deficiency can cause, mainly in chronic alcoholic subjects, the Wernicke encephalopathy and its chronic neurological sequela, the Wernicke-Korsakoff syndrome (WKS). Long-term chronic ethanol abuse results in hippocampal and cortical cell loss. Thiamine deficiency also alters principally hippocampal- and frontal cortical-dependent neurochemistry; moreover in WKS patients, important pathological damage to the diencephalon can occur. In fact, the amnesic syndrome typical for WKS is mainly due to the damage in the diencephalic-hippocampal circuitry, including thalamic nuclei and mammillary bodies. The loss of cholinergic cells in the basal forebrain region results in decreased cholinergic input to the hippocampus and the cortex and reduced choline acetyltransferase and acetylcholinesterase activities and function, as well as in acetylcholine receptor downregulation within these brain regions. In this narrative review, we will focus on the neurochemical, neuroanatomical, and neuropsychological studies shedding light on the effects of thiamine deficiency in experimental models and in humans.
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PMID:Thiamine deficiency induced neurochemical, neuroanatomical, and neuropsychological alterations: a reappraisal. 2423 82

Chronic thiamine deficiency may be responsible for pathologic changes in the brains of alcoholics, and subclinical episodes of this vitamin deficiency may cause cumulative brain damage. In the present work, the chronic effects of ethanol and its association to a mild thiamine deficiency episode (subclinical model) on neocortical and hippocampal acetylcholinesterase activity were assessed along with their possible association to spatial cognitive dysfunction. The results indicate that in the beginning of the neurodegenerative process, before the appearance of brain lesions, chronic ethanol consumption reverses the effects of mild thiamine deficiency on both spatial cognitive performance and acetylcholinesterase activity without having significant effects on any morphometric parameter.
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PMID:Mild thiamine deficiency and chronic ethanol consumption modulate acetylcholinesterase activity change and spatial memory performance in a water maze task. 2477 Sep

The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist.
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PMID:The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat. 2544 52

Arsenic (As) contamination affects hundreds of millions of people globally. Although the number of patients with chronic As exposure is large, the symptoms and long-term clinical courses of the patients remain unclear. In addition to reviewing the literature on As contamination and toxicity, we provide useful clinical information on medical care for As-exposed patients. Further, As metabolite pathways, toxicity, speculated toxicity mechanisms, and clinical neurological symptoms are documented. Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers. A sural nerve biopsy showed the axonal degeneration of peripheral nerves mainly in small myelinated and unmyelinated fibers. Exposure to high concentrations of As causes severe central nervous system impairment in infants, but no or minimal impairment in adults. The exposure dose-response relationship was observed in various organs including neurological systems. The symptoms caused by heavy metal pollution (including As) are often nonspecific. Therefore, in order to recognize patients experiencing health problems caused by As, a multifaceted approach is needed, including not only clinicians, but also specialists from multiple fields.
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PMID:Arsenic Neurotoxicity in Humans. 3133 1


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