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)

Although the central cholinergic deficits are still considered to be of primary importance in Alzheimer's disease, there is great need for an expansion of the pharmacological approach in this illness beyond the simple cholinergic replacement hypothesis. This report focuses on the concept of "combination chemotherapy" in Alzheimer's disease as the next generation of therapeutic strategies. Based on earlier positive findings in Alzheimer patients with the monoamine oxidase B inhibitor, 1-deprenyl, the authors speculate that a combination of physostigmine, the short-acting cholinesterase inhibitor, and 1-deprenyl might be more beneficial than either agent alone. The authors outline a sample paradigm for such combination studies, report preliminary data on the first 16 Alzheimer subjects to have received an initial combination of physostigmine and deprenyl, and point to other possible "combination chemotherapy" strategies for future study.
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PMID:A strategy of "combination chemotherapy" in Alzheimer's disease: rationale and preliminary results with physostigmine plus deprenyl. 128 68

The histochemical and immunocytochemical distribution of some cholinergic and noradrenergic markers was compared in the cerebellum of young adult (3-month old) and aged (24-month old) Wistar rats. A decrease in the density and staining of acetyl cholinesterase (AChE) positive fibers, puncta and Golgi cells was found in both the cerebellar cortex and nuclei of aged rats. The age-related changes in choline acetyltransferase immunoreactivity were less pronounced than the changes in AChE activity. A reduction in the density of catecholamine fluorescent fibers and puncta was observed in the cerebellar cortex during aging. In aged rats the increase in monoamine oxidase (MAO)-A activity was more pronounced than the increase in MAO-B activity.
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PMID:Age-related changes in cholinergic and noradrenergic transmission in the rat cerebellum. A histochemical and immunocytochemical study. 144 23

Assessment was made of the effects of intracerebroventricular (i.c.v.) administration of ethylcholine mustard aziridinium (AF64A) and of the monoamine oxidase (MAO)-B inhibitor L-deprenyl on the acetylcholine (ACh) biosynthetic enzyme choline acetyltransferase (ChAT), on the ACh catabolic enzyme acetylcholinesterase (AChE) and on the density of ACh muscarinic M-1 and M-2 receptor sites. In addition, the effect of AF64A and of L-deprenyl treatment on the localization of AChE activity in the CA-1 and CA-3 fields of the hippocampus was evaluated by combined enzyme histochemistry and microdensitometry techniques. I.c.v. injection of AF64A induced, 4 weeks after administration of the neurotoxin, a remarkable increase of MAO-B activity, and a significant reduction of ChAT and AChE activities in the hippocampus but not in the neostriatum which was used as a reference tissue. Hippocampal muscarinic M-1 receptors were unaffected by AF64A administration, whereas M-2 sites were reduced after neurotoxin injection. Enzyme histochemistry analysis showed that the loss of AChE induced by AF64A was more pronounced in the CA-3 than in the CA-1 field of the hippocampus. Treatment with L-deprenyl induced, from a dose of 11.17 microM/kg/day, a significant reduction of MAO-B activity in the hippocampus. The expression of ChAT and AChE, as well as the density of M-2 receptors, was increased after L-deprenyl administration in the hippocampus but not in the neostriatum. An increase in AChE reactivity was noticeable in the CA-1 and CA-3 fields of the hippocampus of AF64A-injected rats treated with L-deprenyl.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Deficits in cholinergic neurotransmission markers induced by ethylcholine mustard aziridinium (AF64A) in the rat hippocampus: sensitivity to treatment with the monoamine oxidase-B inhibitor L-deprenyl. 149 Apr 32

A comparative study performed in psychosomatic patients (PG) and healthy subjects (HG) reveals several correlations between personality measurements (Minnesota Multiphasic Personality Inventory, Sensation Seeking Scale, Susceptibility to Punishment), and biochemical variables (in serum: MHPG, acetylcholinesterase, calcium, melatonin; and in platelets: monoamine oxidase B, serotonin, calcium proteins). The relationship between some Sensation Seeking subscales and the enzymatic activities evaluated (negative with MAO and positive with AChase) and the opposite sign relationship between serotonin and some scales of MMPI in both groups studied (negative in the PG and positive in the HG) are noteworthy.
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PMID:Neurotransmitter systems and personality measurements: a study in psychosomatic patients and healthy subjects. 290 61

The formamidine pesticide amitraz (AMZ) produces many behavioral and physiological changes in rats. We examined the dose effect and time course of AMZ on motor activity, monoamine oxidase (MAO) activity, and acetylcholinesterase (AChE) activity to evaluate possible neurochemical mechanisms for the behavioral effects of AMZ. For motor activity studies, male Long-Evans hooded rats were tested in photocell activity measurement devices. AMZ produced dose-related decreases in motor activity of rats allowed free access to food and rats maintained at a stable body weight through food restriction. Lowest effective doses of AMZ tested were 1-3 mg/kg, administered 20 min before testing. AMZ appeared to be about three times more potent in food-restricted rats, indicating that amount of body fat may play a significant role in the pharmacokinetics of AMZ. Motor activity returned to control levels over 4-5 days after dosing with 100-200 mg/kg AMZ, whereas recovery was evident the day after administration of low doses (1-30 mg/kg). Inhibition of MAO was measured in whole brain of rats sacrificed at various times after dosing with AMZ. Only greater than or equal to 100 mg/kg AMZ inhibited MAO, which was measurable within 2 hr of dosing and lasted up to 7 days. AMZ appeared to be more selective for type B MAO when given in vivo, although MAO-A was also inhibited at doses greater than or equal to 300 mg/kg. However, no selectivity was indicated by the IC50 values determined in vitro (IC50 = 31 and 28 microM for MAO-A and MAO-B, respectively). AMZ produced only negligible inhibition of AChE at the highest doses administered in vivo or at 10 mM in vitro. These data indicate that while AMZ does inhibit MAO, the dose range over which it produces this action is much higher than that which suppressed motor activity. Thus MAO inhibition is probably not responsible for AMZ-induced alterations in motor activity.
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PMID:Investigations of amitraz neurotoxicity in rats. III. Effects on motor activity and inhibition of monoamine oxidase. 292 11

Administration of delta-sleep-inducing peptide (DSIP) in vivo in a dose of 30 microgram/kg bw brings about MAO-A (substrate-serotonin) activation in synaptosome subfractions and cellular mitochondria from the brain structures (motor cortex, nucleus caudatus, thalamus). Activity of MAO-B (substrate-p-nitrophenylethylamine) and acetylcholinesterase was inhibited negligibly and specifically in subcellular fractions of the test brain structures. The results suggest that DSIP effects the regulatory or modulation function in the synapse. As one of the elements of sleep mechanisms this peptide induces a number of processes, particularly in serotonin metabolism.
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PMID:[Action of the "delta-sleep peptide" on monoamine oxidase and acetylcholinesterase activity in subcellular fractions from different rabbit brain formations in vivo]. 689 65

Depigmentation of neurons in the substantia nigra (SN) is found in patients dying after bone marrow transplantation (BMT). This study examined neurochemical striatal changes related to BMT. Caudate nucleus and putamen of 6 BMT subjects and 10 age-matched controls were analyzed for levels of dopamine (DA), homovanillic acid (HVA), 5-hydroxyindoleamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA), by high pressure liquid chromatography-electron capture detection (HPLC-ECD). In addition, assays of the enzymatic activities of monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) were performed. Cholinergic markers, ChAT and AChE, were reduced in BMT caudate (p < 0.05) but not in the putamen. A recovery toward normal cholinergic enzymatic activity was identified with increased post-transplant survival time. The level of DA was reduced 50% in BMT caudate and putamen while HVA was increased 30%, however, neither reduction achieved statistical significance. Increasing post-transplant survival time correlated with decreased levels of DA in caudate nucleus and putamen in the early post-transplant period, while HVA was increased over the same interval but tended to return to normal levels with increasing survival time. Two-fold increases of BMT caudate 5-HT (p < 0.003) and 5-HIAA were found; similar changes were noted in putamen 5-HT and 5-HIAA (p < 0.0008). Significant increases in MAO-A and B were found in BMT caudate (p < 0.0001 and p < 0.06, respectively) and putamen (p < 0.0005 and p < 0.006, respectively). No statistically significant changes were noted in the 5-HT, 5-HIAA, or MAO A or MAO B with increasing post-transplant survival. Whether these changes are the result of physiologic or toxic effects is unknown.
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PMID:Dopaminergic and serotonergic neurotransmitters in bone marrow transplant patients. 754 3

CBL/57 strain db/db mice exhibit type II (noninsulin-dependent) diabetes. The affected mice are markedly hyperinsulinemic, hyperglycemic, and hypercholesterolemic, and their serum K+ levels are decreased. The brains of the diabetic mice are significantly smaller than those of their lean, control littermates, but the protein concentration is normal. The low brain weight is accompanied by a loss of major fatty acid components within the whole brain, nerve endings, and mitochondrial membranes. Cholesterol levels are low in whole brain but are not significantly different from normal in the synaptosomal membranes. The phospholipid concentration is significantly decreased in whole brain homogenates, crude synaptosomal membranes, and crude mitochondrial membranes of the diabetic mice. In addition, the specific activities of membrane-bound synaptosomal acetylcholinesterase, Na+,K(+)-ATPase, and Mg(2+)-ATPase are decreased in crude synaptosomal membranes of the diabetic mice. The specific activities of carnitine palmitoyltransferase I and carnitine acetyltransferase are significantly increased in the crude mitochondrial fraction isolated from the brains of the type II diabetic mice, whereas the specific activity of pyruvate dehydrogenase complex is decreased. The specific activities of two other mitochondrial enzymes--monoamine oxidase B and citrate synthase--and a cytosolic enzyme--lactate dehydrogenase--are unaltered. The ability to synthesize cyclic AMP is markedly decreased in the brains of the diabetic mice. The concentrations of carnitine and of the amino acids, glutamate, aspartate, glutamine, and serine are unaltered, whereas glycine levels are significantly elevated in the brains of the db/db mice. The data suggest that in vivo the brains of the diabetic mice exhibit a decreased capacity for glucose oxidation and increased capacity for fatty acid oxidation. This hypothesis is supported by the finding that cerebral mitochondria isolated from the db/db mice oxidize [1-14C]palmitate to 14CO2 at a rate almost twice that of control mitochondria. The present findings emphasize the potentially serious alteration of brain metabolism in uncontrolled type II diabetes.
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PMID:Lipid metabolism and membrane composition are altered in the brains of type II diabetic mice. 772 1

Cerebral microvessels from rats were prepared and characterized by their enrichment of specific markers, namely alkaline phosphatase (AP) and tau-glutamyl transpeptidase (tau-GT). Further, it was observed that AP and tau-GT registered marked increase in aged rats. On the contrary, lactate dehydrogenase (LDH) activity decreased with the increasing age. Monoamine oxidase A activity in the microvessels decreased with age whereas MAO-B moved in the reverse direction. No noticeable change was seen in acetyl-cholinesterase activity with increasing age of rats.
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PMID:Permeability function related to cerebral microvessel enzymes during ageing in rats. 873 83

1. AD is believed to stem from dysfunctional cholinergic signaling in the regions of the brain associated with memory and cognition. 2. The occurrence of AD in afflicted individuals correlates with an increase in the accumulation of A beta-rich senile plaques and neurofibrillary tangles in the brain. 3. Currently, the only FDA-approved AD therapies are a group of acetylcholinesterase inhibitors which slow the turnover of the neurotransmitter acetylcholine in the synapse. 4. Many other compounds which target other aspects of the disease, such as reducing neuronal damage and limiting oxidation, are in clinical trials. These include monoamine oxidase (MAO-B) inhibitors, NSAIDs, antioxidants and estrogen, among others. 5. Recent research discoveries have more completely defined the molecular nature of AD, and are generating new approaches for treatment. One idea is to limit the ability of the protein tau to become phosphorylated in hopes that this will limit the formation of neurofibrillary tangles in the brain. 6. A separate approach that is being pursued is to prevent formation and accumulation of A beta plaques. This may be accomplished by either regulating gamma-secretase activity, or using anti-beta-amyloid antibodies to reduce the size of existing plaques. 7. Employing improved procedural and technological approaches during clinical trials, such as bridging studies, dynabridge studies and PET analysis, promises to streamline the drug development process. 8. The use of biomarkers and MRI analysis may be an effective means by which to identify the disease early. Consequently, early intervention treatment therapies may be an effective way of delaying onset of the disease. 9. Long term AD studies, particularly those focusing on the MCI population, are likely to provide statistically valid results using a smaller study population.
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PMID:Review of the next generation of Alzheimer's disease therapeutics: challenges for drug development. 1126 56


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