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)

Baby hamster kidney (BHK) cells were genetically modified to secrete high levels of human nerve growth factor (BHK-hNGF). Following polymer encapsulation, these cells were implanted into the lateral ventricle of four cynomolgus monkeys immediately following a unilateral transection/aspiration of the fornix. Three control monkeys received identical implants, with the exception that the BHK cells were not genetically modified to secrete hNGF and thus differed only by the hNGF construct. One monkey received a fornix transection only. All monkeys displayed complete transections of the fornix as revealed by a comprehensive loss of acetylcholinesterase-containing fibers within the hippocampus ipsilateral to the lesion. Control monkeys that were either unimplanted or received BHK-control (non-NGF secreting) cell implants did not differ from each other and displayed extensive losses of choline acetyltransferase and p75 NGF receptor (NGFr)-immunoreactive neurons within the medial septum (MS; 53 and 54%, respectively) and vertical limb of the diagonal band (VLDB; 21 and 30%, respectively) ipsilateral to the lesion. In contrast, monkeys receiving implants of BHK-hNGF cells exhibited a only a modest loss of cholinergic neurons within the septum (19 and 20%, respectively) and VLDB (7%). Furthermore, only implants of hNGF-secreting cells induced a dense sprouting of cholinergic fibers within the septum, which ramified against the ependymal lining of the ventricle adjacent to the transplant site. Examination of the capsules retreived from monkeys just prior to their death revealed an abundance of cells that produced detectable levels of hNGF in a sufficient concentration to differentiate PC12A cells in culture. These findings support the use of polymer-encapsulated cell therapy as a potential treatment for neurodegenerative diseases such as Alzheimer disease where basal forebrain degeneration is a consistent pathological feature. Moreover, this encapsulated xenogeneic system may provide therapeutically effective levels of a number of neurotrophic factors, alone or in combination, to select populations of neurons within the central nervous system.
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PMID:Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. 785 23

Alzheimer's disease is the most common type of progressive and debilitating dementia affecting aged people. In some early--as well as late--onset familial cases, a genetic linkage with chromosomes 14, 21 (early-onset) or 19 (late-onset) has been indicated. Furthermore, a direct or indirect role has been attributed to normal or structurally altered amyloid beta-protein (concentrated in senile plaques) and/or excessively phosphorylated tau protein (located in neurofibrillary tangles). Degeneration of cholinergic neurons and concomitant impairment of cortical and hippocampal neurotransmission lead to cognitive and memory deficits. Several compounds are being tested in attempts to prevent and/or cure Alzheimer's disease, including tacrine, which has very modest efficacy in a sub-group of patients, and new acetylcholinesterase inhibitors. Pilot experiments have also been launched using nerve growth factor (NGF) to prevent or stabilize the processes of cholinergic pathway degeneration. Alternatively, antioxidants, free radical scavengers and/or non steroidal anti-inflammatory agents may be screened as potential therapies for neurodegenerative diseases induced by multiple endogenous and/or exogenous factors. The recent use of transgenic mice, in parallel with other genetic, biochemical and neurobiological systems, in vivo and/or in vitro (cell cultures), should accelerate the discovery and development of specific drugs for the treatment of Alzheimer's disease.
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PMID:Alzheimer's disease: fundamental and therapeutic aspects. 787 58

The amyloid beta-protein (A beta) of Alzheimer's disease is derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Two secretory proteolytic pathways are involved in the metabolism of beta APP. The major pathway involves cleavage within the A beta sequence and generates carboxyl-truncated derivatives of beta APP which are secreted into the conditioned medium of cells. The minor 'amyloidogenic' pathway results in the production of A beta. Here, cell cultures were used to examine the metabolism of beta APP by tacrine, a centrally active cholinesterase inhibitor reported to improve cognitive deficits. Treatment with tacrine in cells resulted in the drastic inhibition of secretion of the major isoforms of beta APP into the medium. The effect of tacrine can be reversed by washing away the drug from the cells. Treatment with tacrine did not change the level of either HSP-70 or LDH. Thus, the inhibitory effect of tacrine on the secretion of beta APP was not due to the permanent damage or loss of cells as normal release of beta APP could be restored when the drug was washed away.
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PMID:Reversibility of the effect of tacrine on the secretion of the beta-amyloid precursor protein in cultured cells. 789 57

A microdialysis technique was used to investigate the effect of physostigmine (PHY) and heptylphysostigmine (HEP), administered systemically or locally, on the extracellular levels of acetyl-choline (ACh), norepinephrine, dopamine and 5-hydroxytryptamine in the cerebral cortex of the rat. Levels of these neurotransmitters in dialysates were assayed simultaneously with two different high pressure liquid chromatography systems. No cholinesterase inhibitor was added into the probe to increase detection of ACh after systemic administration. Cholinesterase inhibition and its relation to ACh levels were also studied. Systemic administration of two doses of cholinesterase inhibitor [PHY (30 and 300 micrograms/kg) and HEP (2 and 5 mg/kg)] produced a dose-dependent increase in ACh levels. Local perfusion of these drugs through the probe elicited a strong increase in extracellular ACh. HEP produced a longer lasting inhibition of cholinesterase and a more prolonged elevation of ACh in cerebral cortex than PHY. After systemic administration of PHY (both doses), we observed a significant increase of norepinephrine levels. This effect was weaker after HEP. Local administration through the probe did not modify norepinephrine concentration. Dopamine levels were also increased after systemic administration. ONly HEP perfused into the probe elicited a significant increase in extracellular dopamine. Systemic or local administration did not modify 5-hydroxytryptamine levels. These observations suggest a more favorable pharmacological profile for HEP as a potential drug for Alzheimer disease, as compared to PHY.
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PMID:Cholinesterase inhibitor effects on neurotransmitters in rat cortex in vivo. 791 96

Previous histochemical observations in our laboratory have demonstrated the presence of butyrylcholinesterase and an enzymatically altered form of acetylcholinesterase activity in the plaques, tangles and amyloid-containing vessels of Alzheimer's disease. These findings suggested possible interactions between amyloid and cholinesterases. In this study we employed a cholinesterase biochemical assay to determine whether the amyloid precursor protein either had cholinesterase activity itself or influenced the enzymatic activity of cholinesterases. None of the three amyloid precursor sequences used (695, 751, 770, up to 16 micrograms/ml) exhibited any acetylcholinesterase or butyrylcholinesterase activity that could be detected by our method. In addition, none of the amyloid precursor proteins influenced the enzymatic activity of purified acetylcholinesterase or butyrylcholinesterase in a specific manner. It is therefore quite unlikely that amyloid can, by itself, account for the intense cholinesterase activity associated with the pathological lesions of AD.
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PMID:Cholinesterase activity in the plaques, tangles and angiopathy of Alzheimer's disease does not emanate from amyloid. 805 43

Heptylphysostigmine is a new and very promising cholinergic drug for the treatment of Alzheimer disease. A method has been developed for its determination in plasma with a detection limit of 50 pg/ml. The drug was extracted in n-hexane by a simple one-step procedure, after buffering with sodium bicarbonate. Samples were analysed on a 25 cm x 4.6 mm I.D. silica column (5 microns particle size) using a mixture of acetonitrile, methanol and ammonium nitrate as mobile phase. Since this molecule is quite unstable in plasma, pyridostigmine bromide was added to samples to limit the decomposition. Physostigmine was employed as internal standard. The molecule was electrochemically detected by oxidizing potential (+0.75 V). The method was applied to the analysis of blood samples taken from one healthy volunteer administered this drug. In the same subject the inhibition rate of acetylcholinesterase in plasma and red cells was also measured.
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PMID:Determination of heptylphysostigmine in plasma by high-performance liquid chromatography with electrochemical detection. 834 Apr 57

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

Alzheimer disease (AD) is accompanied by a marked loss of acetylcholinesterase (AChE) activity associated with cortical cholinergic axons and cholinoceptive neurons. Simultaneous with this loss, cholinesterase (ChE) activity emerges in AD cortex in the form of AChE and butyrylcholinesterase activity associated with plaques, tangles, and amyloid angiopathy. Our observations have shown that the ChEs associated with the pathological lesions of AD (ADChEs) possess different enzymatic properties and quite possibly are of a different source as compared with the ChEs associated with normal neurons and axons. The ADChEs most likely have noncholinergic functions involved in the pathogenesis of AD. The postulated functions include acting as proteases/peptidases, participating directly in the amyloidogenic processing of the amyloid precursor protein, and causing aberrant growth of neuronal processes. The therapeutic and diagnostic implications of ADChEs are discussed.
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PMID:Cholinesterases and the pathology of Alzheimer disease. 853 19

Alzheimer's disease (AD) is the commonest cause of dementia. Although its ethology is unknown, there is increasing evidence in support of the view that an abnormal degradation of the amyloid precursor protein (APP), perhaps influenced by a number of genetic, tisular or environmental factors, may be the primary cause of the many biochemical and morphological disorders that exist in the associative areas of the brain of these patients. Histopathologically it can be shown by the presence of extracellular senile plaques, intraneuronal fibrilar tangles and neuronal loss. There is no specific pharmacological treatment at present to prevent the disease or its development, in spite of the numerous and diverse drugs studied. Many of these studies are methodologically inadequate. The attempt of activating the cholinergic system has deserved special attention. A reversible inhibitor of acetylcholinesterase, tacrine, has been approved in the United States and other countries for the symptomatic treatment of mild to moderate AD, but its use still arises many questions. Different drug and non drug related interventions may be of great value in the care of these patients, and may influence the specific pharmacological treatments. The complexity and heterogeneity of AD and the multiple factors which may take part in its evolution make it necessary to place special attention on the methodological aspects of the clinical trials with new drugs for the treatment of this disease.
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PMID:[Pharmacological treatment of Alzheimer's disease: present situation and perspectives]. 854 1

We have studied the influence of the extracellular matrix (ECM) on the amount of beta-amyloid precursor protein (APP) and C-terminal amyloid-bearing fragments in 313 fibroblasts. After incubation with ECM components, the cellular APP content of 3T3 cells changed. Besides, different substrata including collagen, fibronectin, laminin, vitronectin, and heparin, determined changes in the amount of a C-terminal 22 kDa-fragment. The regulation of amyloidogenic fragments by the ECM was transient; in fact, when 3T3 cells were plated on tissue culture dishes coated with collagen or vitronectin, maximal levels of the 22 kDa fragment were observed 12 h after plating; in the presence of fibronectin, the maximum level of the amyloidogenic fragment was obtained 36 h after plating. These results indicate that the ECM modulates in a transient way the generation of APP-derived polypeptides containing the amyloid-beta-peptide (A beta). The ECM does not have a generalized effect on 3T3 fibroblasts, because no significant differences in cell attachment, growth rate, whole-cell polypeptide pattern beta 1 integrin and alpha-tubulin levels were observed on cells grown on various matrix proteins. Laminin, collagen, and heparin also influence the level of an amyloidogenic fragment of 35 kDa in Neuro 2A neuronal cells, without a significant change in the neuronal marker acetylcholinesterase. In this case, however, a long-lasting response to ECM molecules was observed. These observations provide evidence that ECM molecules influence APP biogenesis, including the generation of amyloidogenic fragments containing the A beta peptide. Our studies might prove significant to understand the localized increment of beta-amyloid deposition in selected areas of the brain of Alzheimer's patients.
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PMID:Extracellular matrix regulates the amount of the beta-amyloid precursor protein and its amyloidogenic fragments. 859 96


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