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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

In this study we examined the question whether cholinesterase inhibitors (ChEI) could alter the release of amyloid precursor protein (APP) from superfused brain cortical slices of the rat following electrical as well as pharmacological stimulation with bethanechol (BETHA). Three ChEI, both reversible and irreversible were tested for their ability to enhance the release of non-amyloidogenic soluble derivatives (APPs). These included physostigmine (PHY), heptyl-physostigmine (HEP) and 2,2-dichlorovinyldimethyl phosphate (DDVP), at the concentrations producing cholinesterase (ChE) inhibition ranging from 5% to 95%. All three ChEI elevated APPs release significantly above control levels. Electrical field stimulation significantly increased the release of APPs within 50 min. Similar increase was observed after muscarinic receptor stimulation with BETHA. Tetrodotoxin (TTX) completely blocked the effect of electrical stimulation. These findings suggest that long-term administration of ChEI to Alzheimer's disease (AD) patients may have a neuroprotective effect by activating normal APP processing and decreasing the formation of amyloidogenic APP products.
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PMID:The effect of cholinesterase inhibitors on the secretion of APPS from rat brain cortex. 862 19

Physostigmine, a reversible and nonselective cholinesterase inhibitor, administered by steady-state, continuous intravenous infusion to carefully selected subjects with mild-moderate Alzheimer disease, produced significant but modest improvement in memory in five of nine subjects. Drug dosing was limited by the occurrence of adverse effects. Apparent tolerance to adverse effects was observed in two subjects when the dose of physostigmine was escalated slowly over at least 2 weeks. Steady-state cholinesterase inhibition by physostigmine appears to produce sustained cognitive improvement in some subjects with Alzheimer disease without substantially altering its therapeutic index.
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PMID:Treatment of Alzheimer disease by continuous intravenous infusion of physostigmine. 874 12

Recent studies implicate that excessive amyloidogenic pathway of amyloid precursor protein (APP) processing may be the final common pathway involved in the pathogensis of AD. In attempts to identify the proteases or factors leading to excessive amyloid deposition, we evaluated the potential role of acethylcholinesterase (AChE) and its associated protease for amyloidogenic processing of APP in vitro. Prolonged incubation of a recombinant APP770 with AChE produced several amyloidogenic fragments accumulating a relatively stable a 18 kDa A beta (amyloid beta-protein) bearing carboxy terminal peptide, which was further degraded by an increased concentration of AChE. Protease inhibitory profiles confirmed the trypsin-like serine protease activity present in AChE preparation. This observed APP processing was significantly enhanced by Ca2+, Mg2+, or Mn2+ at 1 mM concentration and modulated in concentration dependent manners by metal ions such as Ca2+, Zn2+, Fe2+/Fe3+, Al3+, or a tacrine, a centrally active cholinesterase inhibitor. Our data imply that AChE and its associated protease may be involved in the generation a 18 kDa amyloidogenic peptide under certain physiological condition in vivo and that the gradual changes in their proteolytic activities or locations and the locally disturbed metal homeostasis could be factors associated with abnormal accumulation of APP, eventually leading to amyloid deposition in AD brain. In addition, zinc or tacrine treatment of AD patients with high dosage or in the long term may have effects on the process of amyloidogensis.
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PMID:Amyloidogenic processing of Alzheimer's amyloid precursor protein in vitro and its modulation by metal ions and tacrine. 876 43

Substantial evidences suggest that the increased cerebral deposition, and neurotoxic action of the beta-amyloid peptide, the major constituent of senile plaques, may represent the underlying cause of the cognitive deficits observed in Alzheimer's disease. Herein, we attempted to verify this hypothesis by inducing a potential Alzheimer's-type amnesia after direct intracerebroventricular administration of aggregated beta 25-35-amyloid peptide in mice. In this aim, mnesic capacities were evaluated after 6-13 days, using spontaneous alternation in the Y-maze, step-down type passive avoidance and place learning in a water-maze. Pretraining administration of aggregated beta 25-35 peptide induced dose-dependent decreases in both alternation behaviour and passive avoidance, at doses of 3 and 9 nmol/mouse. A reduced but still significant impairment was observed when the peptide was not aggregated, or 'aged', by preincubation for 4 days at 37 degrees C. The beta 1-28 peptide, at 3 nmol/mouse, also induced a marked decrease in step-down latency. Posttraining, but not preretention, administration of beta 25-35 peptide also significantly impaired learning. The beneficial effects of cholinergic agents on beta 25-35-induced amnesia was examined using the cholinesterase inhibitor tacrine (THA, 1.3 and 4.3 mumol/kg i.p.) and the nicotinic receptor agonist (-)-nicotine (NIC, 0.06 and 0.2 mumol/kg i.p.). Both drugs induced a dose-dependent abrogation of the beta 25-35-induced decreases in alternation behaviour and passive avoidance. Furthermore, THA, at 1.3 mumol/kg, and NIC, at 0.2 mumol/kg, also reversed the beta 25-35-induced impairment of place learning and retention in the water-maze. Histological examination of Cresyl violet-stained brain sections indicated a moderate but significant cell loss within the frontoparietal cortex and the hippocampal formation of mice treated with aged beta 25-35 peptide (9 nmol). Examination of Congo red-stained sections in the same animals demonstrated the presence of numerous amyloid deposits throughout these brain areas. These results confirm that the deposition of beta-amyloid peptide in the brain is in some way related to impairment of learning and cholinergic degeneration and suggest that the [25-35] fragment of the beta-amyloid protein, sufficient to induce neuronal death in cultures, also induces an Alzheimer's-type amnesia in mice.
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PMID:Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. 882 55

The senile plaque in Alzheimer's disease (AD) consists mainly of the amyloid beta-peptide (A beta) derived from a family of large integral membrane glycoproteins, beta-amyloid precursor proteins (beta APP). Soluble derivatives of beta APP generated by the proteolytic processing of full-length beta APP are normally secreted into the conditioned medium of cultured cells. Here we have investigated the possibility that the processing of beta APP can be regulated by the cholinesterase inhibitors physostigmine and tacrine. Both drugs mildly improve cognitive functions in some patients with AD. We analyzed the level of beta APP in glial, neuroblastoma, and pheochromocytoma cells by immunoblotting cell lysates and conditioned media using a monoclonal antibody, MAb22C11. The levels of soluble beta APP derivatives normally present in conditioned media were severely inhibited by treating cells with tacrine but not with physostigmine. Whereas the treatment of cells with tacrine resulted in a small decrease in the intracellular levels of beta APP, treating cells with physostigmine resulted in a slight increase in the intracellular levels of beta APP compared to untreated cells. The effect of tacrine on the secretion of beta APP was not affected by cotreating cells with muscarinic agents, staurosporine, or the calcium ionophore. Our results suggest that a decrease in the secretion of beta APP by tacrine did not depend on its anticholinesterase activity and that tacrine operates via a noncholinergic mechanism.
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PMID:Differential effect of tacrine and physostigmine on the secretion of the beta-amyloid precursor protein in cell lines. 883 81

This study addresses the developmental regulation of amyloid precursor protein (APP) fragments comprising the amyloid-beta peptide (AP) and the amyloid-promoting factor acetylcholinesterase (AChE) in a mouse neuronal cell line (Neuro-2a). Results indicate that a 35-kDa amyloidogenic fragment of APP and the major molecular forms of AChE (G1 and G4) in Neuro-2a cells significantly increase with increasing levels of cell confluence. The foregoing molecules undergo further increases when neuroblastoma cells differentiate in the presence of dibutyryl cAMP. In contrast, a 17-kDa fragment of APP and butyrylcholinesterase were not affected by cell confluence or differentiation. These findings are the first to indicate that a selective Abeta-containing fragment of APP is subject to developmental regulation. Moreover, our data show that the 35-kDa fragment and AChE forms respond in parallel to the same developmental stimuli, i.e., cell confluence and differentiation. This points to the existence of a functional relationship between both molecules, a notion that is consistent with the potential role that has been ascribed to AChE in both APP processing and the formation of amyloid deposits in Alzheimer's brains.
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PMID:Amyloid precursor protein fragment and acetylcholinesterase increase with cell confluence and differentiation in a neuronal cell line. 894 Feb 53


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