Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in Alzheimer's disease. We had found that traditional AChE inhibitors such as BW284C51, tacrine and physostigmine were more potent inhibitors of the AChE in normal axons and cell bodies than of the AChE in plaques and tangles. We now report that the reverse pattern is seen with indolamines, 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 neurons and axons. This shift in enzymatic affinity may lead to the abnormal protein processing which is thought to play a major role in the pathogenesis of AD. The availability of pharmacological and dietary means for altering brain indolamines raises novel therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer's disease.
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PMID:Protease inhibitors and indolamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer's disease. 823 15

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.
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PMID:Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease. 842 6

In a group of patients with endometriosis and in a control group of healthy women, the polymorphism of the following systems were studied: ABO and RH blood-group systems; serum proteins haptoglobin (HP), transferrin (TF), vitamin D-transporting protein (GC), protease inhibitor (PI), and the third component of the complement (C3); serum enzymes-amylase of the loci 1 and 2 (AMY1 and AMY2), pseudocholinesterase (E2), and alkaline phosphatase (PP); erythrocytic enzymes-acid phosphatase (ACP1), phosphoglucomutase (PGM1), superoxide dismutase (SOD-A), esterase D (ESD), and glyoxalase (GLO1). Statistically significant differences between the groups compared were established for five genetic systems: ABO, E2, C3, TF, and PGM1. Among patient with endometriosis, the rare alleles of the locus ESD-ESD5 and ESD7-were found, along with ESD 5-5 homozygotes. Several genetic loci can be involved in the pathogenesis of endometriosis; their products can be specifically realized due to peculiarities of biochemical reactions in the organisms of people predisposed to this pathology.
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PMID:[Genetic aspects of endometriosis: features of the distribution of polymorphic gene frequencies]. 910 63

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a larger beta-amyloid precursor protein (betaAPP). The majority of betaAPP is processed by either a secretory or lysosomal/endosomal pathway. Soluble derivatives of betaAPP (sAPP) and A beta generated by the proteolytic processing of full-length betaAPP are normally secreted into the conditioned medium of cultured cells. Tacrine, a centrally active potent cholinesterase inhibitor that has been shown to improve cognitive functions in some patients with AD, inhibits the secretion of sAPP. Here we have investigated whether leupeptin, a lysosomal protease inhibitor, could influence this effect of tacrine. We analyzed levels of betaAPP derivatives in cultured HeLa cells by immunoblotting cell lysates and conditioned media using the monoclonal antibody 22C11. Levels of sAPP normally present in conditioned media were severely reduced by treating cells with tacrine. The treatment of cells with tacrine resulted in a small decrease in the intracellular levels of betaAPP. The effect of treating the cells with tacrine did not depend upon the growing state of the cells as a similar effect was observed when the drug was added either during initial plating of the cells or after the attachment of the cells. The effect of tacrine was not affected by preincubating the cells with low serum in the culture medium. The treatment of cells with tacrine plus leupeptin reduced the secretion of sAPP in the medium to the same degree as did the treatment with tacrine alone, suggesting that the tacrine-mediated inhibition of sAPP release may not involve leupeptin-sensitive proteolytic pathways. The results suggest that the inhibitory effect of tacrine on sAPP secretion is not due to the proteolytic cleavage of the holoprotein in the medium.
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PMID:The effect of tacrine and leupeptin on the secretion of the beta-amyloid precursor protein in HeLa cells. 936 5

The present study was undertaken to investigate the beneficial effect of HIV protease inhibitor Indinavir on memory deficits associated with experimental dementia of Alzheimer disease's (AD) type. Dementia was induced in Swiss albino mice by administration of Celecoxib (100 mg kg(-1) orally, daily for 9 days) or Streptozotocin (3 mg kg(-1) administered intracerebroventricularly on 1st and 3rd day) and the cognitive behaviors of Swiss albino mice were assessed using Morris water maze test. Brain acetyl cholinesterase (AChE) activity was measured by Ell Mann's method. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively to assess total oxidative stress. Donepezil (0.1 mg kg(-1) i.p.) served as positive control in the present investigation. Celecoxib as well as Streptozotocin (STZ) produced a significant loss of learning and memory. Indinavir (100 and 200 mg kg(-1) orally) successfully attenuated Celecoxib as well as STZ induced cognitive deficits. Higher levels of brain AChE activity, TBARS and lower levels of GSH were observed in Celecoxib as well as STZ treated animals, which were significantly attenuated by Donepezil and Indinavir. Study highlights the potential of Indinavir in memory dysfunctions associated with dementia of AD.
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PMID:Exploitation of HIV protease inhibitor Indinavir as a memory restorative agent in experimental dementia. 1834 89

Organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the world. Poisoning includes acute cholinergic crisis as a result of AChE inhibition, intermediate syndrome (IMS) due to neuromuscular necrosis and organophosphate-induced delayed neuropathy (OPIDN) due to inhibition of neuropathy target esterase (NTE). Standard treatment for acute poisoning involves administration of intravenous atropine, oxime 2-PAM to counter AChE inhibition and diazepam for CNS protection. However clinical trials showed ineffectiveness of the standard therapy regimen. Although new oximes that can reactivate both peripheral and cerebral AChE and other prophylactic agents such as human serum butyrylcholinesterase (Hu BChE), sodium bicarbonate, huperzine A (a reversible ChE inhibitor) with imidazenil (a GABAA receptor modulator) have been proved effective in animal models, systematic clinical trials in patients are warranted. For IMS which is non-responsive to standard therapy, supportive therapy specifically artificial respiration followed by recovery is indicated. For OPIDN which has a different target (NTE) than AChE, standard therapy is ineffective. However neuroprotective drugs such as corticosteroids proved partially effective. Pretreatment with protease inhibitor PMSF has been shown to protect the aging of NTE and prevent the development of delayed symptoms in hens. Since the biology of NTE is being explored, new pharmacological agents should be developed in future. OP pesticide poisoning is a serious condition that needs rapid diagnosis and treatment. Since respiratory failure is the major reason for mortality, artificial respiration, careful monitoring, appropriate treatment and early recognition of OP pesticide poisoning may decrease the mortality rate among these patients.
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PMID:Pharmacological agents in the prophylaxis/treatment of organophosphorous pesticide intoxication. 2092 49

In Alzheimer's disease, histochemically visualized cholinesterases with altered pH optimum for activity and inhibitable by indoleamines and the protease inhibitor bacitracin emerge in association with plaques and tangles. It has been suggested that these cholinesterases may participate in the pathologic process. However, it is not known whether the properties of cholinesterases observed in Alzheimer's disease are due to requirements of histochemical procedures or actual biochemical properties of these enzymes. Using biochemical assays of acetylcholinesterase and butyrylcholinesterase activities, we demonstrate here that serotonin and bacitracin result in a significantly greater and dose-dependent inhibition of cholinesterases in Alzheimer's disease cortex when compared with age-matched controls. In contrast, variations in pH did not distinguish cholinesterases in Alzheimer's disease and control cortex. We also confirmed significant reduction of acetylcholinesterase activity in Alzheimer's disease cortex and increased butyrylcholinesterase activity that only approached significance. We conclude that inhibition by indoleamines and bacitracin is a biochemical characteristic of a proportion of cholinesterases in Alzheimer's disease that most likely represents the pool associated with plaques and tangles. Most of the available cholinesterase inhibitors are relatively incapable of inhibiting cholinesterases associated with plaques and tangles. The findings of the present investigation open the way for attempts to isolate cholinesterases associated with plaques and tangles and design or discovery of inhibitors specifically targeted to cholinesterases in these lesions.
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PMID:Biochemical differentiation of cholinesterases from normal and Alzheimer's disease cortex. 2124 53