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)

The sc LD50s (mumol/kg) in rats for diisopropylfluorophosphate (DFP), Tabun, Sarin, and Soman were 14.5, 1.9, 1.4, and 0.88, respectively. The relative potency was as follows: DFP less than Tabun less than Sarin less than Soman (1:7.6:10.4:16.4). The relative potencies correlated with the in vitro acetylcholinesterase (AChE) inhibition (in terms of the IC50) by these compounds, in whole brain homogenates or the purified bovine erythrocyte AChE. There was a dose versus time for mortality relationship for all four compounds; the average time for death decreased with increase in dose. However, there was no correlation between time for death and the extent of AChE inhibition. The striatal as well as other regional (medulla, diencephalon, cortex, and cerebellum) AChE activity was inhibited over 90% of the control, by the lethal doses of these compounds. None of the lethal or sublethal doses had any apparent effect on choline acetyltransferase (CAT) or GABA-transaminase activities. Glutamic acid decarboxylase activity was increased by Soman, Sarin, and Tabun at certain lethal doses but was not affected by DFP even at the lethal dose. The results indicate that (a) the acute toxicity of organophosphate acetylcholinesterase inhibitors is directly related to the inhibition of AChE though there is a wide difference in their potency; (b) a substantial inhibition of AChE activity (over 90% of control) is necessary for lethality to ensue after an acute exposure and the margins between lethal and nonlethal doses are extremely small; and (c) qualitative differences seem to exist among the various organophosphates in affecting noncholinergic neurotransmitter enzymes.
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PMID:An assessment of comparative acute toxicity of diisopropyl-fluorophosphate, tabun, sarin, and soman in relation to cholinergic and GABAergic enzyme activities in rats. 647 98

In the present paper the behaviour of the enzymes monoaminoxidase, GABA-transaminase, acetylcholinesterase, nonspecific cholinesterase, A-, B-, C-esterase and acid phosphatase was investigated by histochemical and biochemical methods for 1 min, 1, 4 and 24 h after a "brightness-discrimination" of male wistar rats in a Y-chamber. Learning induced significant changes of activity of the B-esterase in the hippocampus region 4 h (increase of 30%) and 24 h (decrease of 25%) and of the acetylcholinesterase in the cingular cortex 4 h after training (increase of 38%) are to be observed and regarded and discussed as hints for a changed protein synthesis (B-esterase) or altered synaptic activity (acetylcholinesterase). On the strength of these results and various findings in the literature it may be reputed as sure, that the protein synthesis of the cells of hippocampus in evident. Certain proteins show increased rates of synthesis by the influence of a learning experiment. These proteins are at least partially enzymes, serving as extension of the protein synthesis apparatus of the neurons and may be regarded as part mechanism of the intracellular regulation of the synaptic connectivity.
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PMID:[Histochemical and biochemical study of the hippocampus and neocortex of the wistar rat. II. The activity of carboxylic acid esterases and transmitter enzymes after a learning experiment]. 677 55

Trimethyltin (TMT) induced a dose-dependent antinociceptive and hypothermic effect in mice. Antinociception was not attenuated by naloxone but was reversed by atropine. TMT, however, was ineffective in displacing (3H)-QNB binding in vitro and did not affect (3H)-QNB binding or acetylcholinesterase activity after in vivo administration. The ethyl ester of nipecotic acid, a specific inhibitor of synaptosomal GABA uptake, exerted a similar antinociceptive effect that could be blocked by atropine. The GABA receptor antagonist bicuculline attenuated antinociception induced by TMT and nipecotic acid ethyl ester but not by morphine or oxotremorine. Gamma-Vinyl GABA, an irreversible inhibitor of GABA metabolism, prolonged TMT but not morphine-induced antinociception. In contrast, neither the dose-response nor the time course of TMT-induced hypothermia were affected by any of the drugs tested. The findings suggest that the GABAergic system may be involved in TMT induced antinociception; however, the mechanism responsible for the hypothermic effect of TMT is not apparent.
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PMID:Antinociceptive and hypothermic effects of trimethyltin. 689 Jun 11

More than a decade of scientific inquiry into the biochemistry of schizophrenia has been organized by the dopamine hypothesis. The evidence that neuroleptics reduce brain dopamine activity is compelling and derives from both human and animal studies. In addition, agents which enhance brain dopamine activity, such as amphetamine or cocaine, can cause a syndrome that can be indistinguishable from acute paranoid schizophrenia. However, a major problem with the dopamine hypothesis is the lack of strong direct evidence of altered dopamine concentrations or metabolism when measured in large groups of schizophrenic subjects. The idea that schizophrenia is more than one illness is an old concept, but it finds increasing support in new studies of the clinical phenomenology, genetics, and biochemistry of schizophrenic patients. The revival of the concept of multiple forms of schizophrenia, in turn, has fostered the development of new biochemical hypotheses of the disorder. These hypotheses propose that neurotransmitters, other than dopamine, may be involved in schizophrenic symptoms. Reports of elevated concentrations of norepinephrine is specific areas of the brain and in the spinal fluid have led to the hypothesis that norepinephrine may be involved in schizophrenia. At least two groups of investigators have suggested that phenylethylamine might be involved in schizophrenia. In part, this proposal is based on the structural and pharmacological similarities of phenylethylamine and amphetamine. gamma-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter. Evidence for the inhibitory influence of GABA-ergic neurons on dopaminergic neurons has led to the hypothesis that decreased GABA-ergic activity may be involved in producing schizophrenic symptoms. Studies with the reversible acetylcholinesterase inhibitor physostigmine and the dopamine agonist methylphenidate have led to the suggestion that acetylcholine and dopamine imbalance may be involved in schizophrenia. This hypothesis is one example of the idea that altered balance between several neurotransmitters may underlie schizophrenia. The recent discovery of the endorphins has led to speculations about the possible role of these substances in schizophrenia. Both an excess and a deficiency of endorphin activity have been implicated in schizophrenia, and speculative evidence has been used to support both hypotheses. The ultimate aim of the search for biochemical defects in schizophrenia is the development of rational drug treatments which will correct these defects and in doing so, these drugs will provide effective treatments for patients with schizophrenic symptoms.
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PMID:Biochemistry and the schizophrenia. Old concepts and new hypothesis. 700 86

The distribution of GABA fibers within the dentate gyrus was immunohistochemically examined following lesions of the entorhinal cortex in the adult rat. A major change in the pattern of the GAD immunoreactive fibers within the molecular layer, characterized by a marked increase in the density of fibers in the outer molecular layer, was observed. This change in the lamination of the dentate GABA fibers following entorhinal lesions appeared very similar to the changes which occur in acetylcholinesterase staining following entorhinal denervation of the dentate. These results provide morphological support for the sprouting of GABA fibers in the dentate gyrus in response to perforant path destruction.
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PMID:Immunohistochemical demonstration of plasticity in GABA neurons of the adult rat dentate gyrus. 704 74

Kainic acid administration into the cerebellar dorsal lobe of the goldfish causes selective degeneration of some neuronal types. Stellate and Golgi neurons are very sensitive to the neurotoxin and undergo rapid degeneration. On the basis of their differential responses to kainic acid, Purkinje cells can be divided in two distinct sub-populations (i.e. sensitive and insensitive neurons). The degenerative changes of the Purkinje neurons are in addition remarkably slow in comparison with the same cells in mammals or with stellate and Golgi neurons in the goldfish. Granule cells, as well as the cerebellar afferent fiber system, are not significantly affected. Six days after kainic acid administration, the level of glutamate decarboxylase in the cerebellar dorsal lobe drops to about 40% of the control value. This result suggests that the neurons sensitive to kainic acid neurotoxicity are, at least in part, GABAergic. Light- and electron-microscopic autoradiography of cerebellar elements selectively accumulating [3H]GABA, supports this idea. Moderate decreases of acetylcholinesterase and protein content were also noticed in the kainic acid-treated cerebellar dorsal lobe.
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PMID:Neurotoxic effect of kainic acid on ultrastructure and GABAergic parameters in the goldfish cerebellum. 717 84

A membrane vesicle preparation was used to examine characteristics of the human placental cholinergic system. Plasma membrane vesicles were prepared from the microvillous surface of the human placental syncytiotrophoblast. Membranes were purified 18 -to 20-fold as indicated by 5'-nucleotidase activity. Vesicle cholinesterase activity was enriched and had a substrate preference consistent with that of acetylcholinesterase (acetylcholine greater than acetyl-beta-methylcholine greater than butyryl-choline). Choline acetyltransferase specific activity was reduced 80%. The synthetic muscarinic ligand, [3H]-quinuclidinyl benzilate (QNB), was used to identify two classes of muscarinic cholinergic binding sites. The dissociation constant of QNB binding was 80 pM and 30 nM for the two sites. The sites were saturable and bound 9 fmoles and 910 fmoles per mg protein for the high and low affinity sites, respectively. Specific binding was inhibited by scopolamine, atropine, carbamylcholine (CCH), and diphenhydramine, but not by non-muscarinic ligands-i.e. GABA, glycine, d-amphetamine, kappa-bungarotoxin and nicotine. The cholinergic agonist CCh had no effect on active AIB transport, although pharmacologic doses (lmM) of atropine, scopolamine and lidocaine reduced Na-gradient active transport of kappa-aminoisobutyric acid (AIB). No effect on Na-independent AIB transport was observed. Thus, these drugs apparently reduced AIB uptake through their shared local anesthetic activity and not through a central cholinergic mechanism. In contrast, CCh was able to stimulate Ca2+ uptake by the vesicles in a dose-dependent manner paralleling its ability to inhibit QNB binding. The CCh-stimulated Ca2+ uptake was inhibited by scopolamine, implying its mediation via cholinergic-type binding sites. The membrane vesicle preparation therefore provides a useful model for examination of the role of the human placental cholinergic system.
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PMID:Syncytiotrophoblast membrane vesicles: a model for examining the human placental cholinergic system. 733 61

Following sequential intraocular transplantations of areas containing NE cell bodies (locus coeruleus or superior cervical ganglion) and of NE fiber target areas (hippocampus), both pieces mature in a manner analogous to that observed for individual transplants. NE-containing nerve fibers, derived from either LC or SCG transplants, can be seen to invade the hippocampal formation. When LC is used, the invading fibers markedly hyperinnervate the hippocampus while SCG-derived fiber densities approximate those seen with innervation from the adrenergic ground plexus of the iris. Electrophysiological recordings from neurons in the LC reveal an atropine-sensitive excitatory response to illumination, suggesting innervation of the LC by cholinergic nerve fibers from the iris. This is supported by the fact that dense cholinesterase-positive staining can be found in the LC piece. Application of an epileptogenic agent, such as penicillin, results in a marked excitation of neurons in the LC without inducing epileptiform activity in the hippocampus. In contrast, single hippocampal grafts seize readily after penicillin. Local application of the inhibitory agent GABA into the LC allows penicillin-induced epileptiform activity to generate in the hippocampus, suggesting that functional inhibitory innervation develops between NE fibers derived from LC and pyramidal neurons in the hippocampus. Supporting this, subsequent excitation of LC neurons by iontophoresis of glutamate terminates the hippocampal seizure. Prior administration of reserpine (2.5 mg/kg) disrupts the inhibitory influence of LC innervation on the hippocampal EEG following penicillin. After reserpine, the hippocampal portions of double grafts behave like single hippocampal transplants. It is concluded that sequential transplantations of cell body and target regions of the CNS to the anterior chamber of the eye creates a functional, yet isolated, neuronal pathway which can be utilized to study the development of neuronal connections.
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PMID:Conditions for adrenergic hyperinnervation in hippocampus: II. Electrophysiological evidence from intraocular double grafts. 739 24

Charles River CD male rats were randomly divided into 3 groups of five each and placed on folate deficient, folate excess, and control diets respectively. glutamate decarboxylase GAD gamma-amino-butyrate aminotransferase (GABA-T), choline acetltransferase (ChAc), and acetylcholinesterase (AChE) were assayed in the rat brains after 6 weeks of dietary treatment. Neither folate deficiency nor folate supplementation influenced the enzymes associated with GABA and acetylcholine metabolism.
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PMID:Dietary folic acid and the activity of brain cholinergic and gamma-aminobutyric acid (GABA) enzymes. 740 19

Neurochemical analysis of neuronal function was undertaken by measuring the activities of cholinacetyltransferase (CAT), acetylcholinesterase (AChE), and glutamic acid decarboxylase (GAD), in the telencephalon, brain stem and cerebellum of the mouse. Cholinergic activity was first expressed in the 10-day embryonic brain stem, which showed a relatively high CAT activity at birth. Postnatal brain stem development was characterized by a rapid and parallel increase in CAT and AChE. Although AChE peaked at 1 month, CAT activity was no achieved until 1 year. Acetylcholine synthesis was initiated in the 12-day embryonic telencephalon and a steady age-related increase in CAT was maintained until birth. A lag in both CAT and AChE activities was recorded during the first week of postnatal telencephalon development. Cerebellar CAT was low at birth, and increased irregularly to reach a maximum by 1 month. In contrast, postnatal cerebellar AChE activity increased steadily over the same time period. The GABA-ergic neuronal system matured rapidly in each brain region, and was unaffected by aging. Although the brain stem precociously expressed cholinergic activity, it wa the region most susceptible to deterioration during aging. Telencephalon CAT activity was unaffected by aging and in the cerebellum, a significantly reduced level of CAT was only found in truly senescent animals. The decreased cholinergic function during senescence was not due to either increased proteolysis or to alteration in the molecular form of the cholinergic enzymes.
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PMID:Neurotransmitter enzymes in telencephalon, brain stem and cerebellum during the entire life span of the mouse. 742 Dec 99


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