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PubMed1994

Cholinesterase inhibitor effects on neurotransmitters in rat cortex in vivo.

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.

Acetylcholine↗

PubMed1994

[New locus of cholinesterase (E3) expressed in human milk].

Analysis of structural variation in enzymes and other proteins of human milk revealed polymorphism of the protein exhibiting cholinesterase activity. The distribution of cholinesterase activity zones after electrophoresis of milk proteins in polyacrylamide gel differs from the pattern typical for serum cholinesterase. Samples of milk taken from 132 recently confined Russian women, which were obtained from Moscow district maternity hospital, were subjected to population analysis. Four phenotypes of the locus designated as E3, have been identified: 1-1, 2-1, 2-2 and 3-1. Preliminary visual evaluation of the electrophoretic pattern allows as to differentiate phenotypes in the following order according to enzyme activity: 2-2 > 2-1 > 3-1 > 1-1. It seems most probable that the revealed variants of cholinesterase E3 are determined by three alleles of one autosomic locus with the following frequencies: E3*1 = 0.8296; E3*2 = 0.1629 and E3*3 = 0.0075. The obtained distribution of E3 phenotypes is in good agreement with the expected one with chi 2(1) = 0.9378.

Cholinesterases↗

PubMed1975

Dual significance of hepatic cholinesterase as an index of liver involvement and state of protein-calorie malnutrition.

159 cases of different forms of PCM (K.W.O., marasmic K.W.O., marasmus & nutritional oedema together with 20 cases normal healthy controls were selected. Serum, red blood cells and liver cholinesterases were estimated together with serum total protein and serum albumin. Pathological liver examination was done for every case, some cases from each group were followed-up till clinical recovery and the same investigations were done to them. The results indicate that the serum and hepatic pseudo-cholinesterase activity parallels directly the serum albumin (not the total proteins) as well as the pathological changes in the liver. The diminution in enzymatic activities and serum proteins coincides with the severity of the liver affection in the various forms of PCM. Insignificant change in true cholinesterase was demonstrated in all cases studied. Follow-up studies in a number of cases till clinical recovery revealed the return to normal of enzymatic activity and serum albumin is concomitant with restoration of normal pathological liver finding. The significance of changes in serum and liver cholinesterase activities as indices of the extent of liver involvement as well as their diagnostic and prognostic values was discussed.

Blood Proteins↗

PubMed1993

Improved colorimetric method for cholinesterase activity.

A modified colorimetric method for the estimation of cholinesterase activity has been worked out using two different substrates, acetylthiocholine iodide for total cholinesterase and a specific substrate, butyrylthiocholine iodide for pseudocholinesterase in the same sample. This is a modification of the method described by Voss and Sachsse (1970) wherein acetylthiocholine iodide was used for both total and pseudo cholinesterase activities. The pseudocholinesterase obtained with acetylthiocholine iodide was significantly higher (P < 0.0001) than that with butyrylthiocholine iodide either in whole blood or serum samples. Acetylthiocholine iodide while reacting with pseudocholinesterase in serum or plasma samples might also be interacting with the small quantities of acetylcholinesterase present. It is therefore suggested that butyrylthiocholine iodide and acetylthiocholine iodide may be used to determine pseudocholinesterase and total cholinesterase activities respectively. The use of two substrates with a few more alterations in the experimental conditions increased the validity of this simple and rapid colorimetric method.

Acetylthiocholine↗

PubMed1996

Correlation between the severity of symptoms in organophosphorus poisoning and cholinesterase activity (RBC and plasma) in humans.

This study was undertaken to examine the correlation, if any, between the inhibition of red blood cell cholinesterase (RBC ChE), plasma cholinesterase (PChE) and cerebrospinal fluid acetyl cholinesterase (CSF AChe) and the severity of symptoms in patients poisoned with organophosphorus (OP) compounds. Baseline values of the cholinesterases (RBC, Plasma & CSF) were established in our laboratory using a modified colorimetric method. OP poisoned patients were divided into 3 groups - mild, moderate and severe based on clinical symptoms. We observed a severity dependent inhibition of both RBC ChE and PChE, in acute poisoning. Sequential post exposure estimations of the ChEs upto 5 days not reveal any rise in the values though there was substantial clinical improvement. Our findings therefore indicate that the correlation of ChE values with severity of symptoms are applicable only in the initial stages of acute poisoning. AChE could not be detected in CSF in two severely neurotoxic patients who subsequently expired. The clinical significance of this observation needs to be examined further.

Cholinesterases↗

PubMedDate not supplied

In vitro protection of plasma cholinesterases by metoclopramide from inhibition by paraoxon.

Metoclopramide (MCP) is a dopamine receptor antagonist and serotonine receptor agonist widely used as an antiemetic and gastric prokinetic drug. In addition MCP is a reversible inhibitor of cholinesterases from human central nervous system and blood. MCP may have a cholinesterase protective effect against inhibition by organophosphates. The purpose of the study was to quantify "in vitro" by means of the IC(50)-shift the extent of MCP conferred protection, using paraoxon (POX) as an inhibitor. POX is a widely used organophospate responsible for a large number of accidental or suicidal exposures. Cholinesteratic activities (ChE) (with acetyl-thiocholine (A) and butyryl-thiocholine (B) as substrates) in human plasma were measured photometrically in the presence of different POX concentrations and IC(50) was calculated. Determinations were repeated in the presence of increasing MCP concentrations. It appears that the shift induced by the presence of MCP increases with the MCP concentration in a linear manner. In the presence of a clinically easily achievable plasma concentration of 1 micro M MCP the IC(50) of POX for ChE 'shifts' by a factor of approximately 2-3. The protective effect of metoclopramide on cholinesterases could be of practical relevance in the treatment of paraoxon poisoning. We conclude that in vivo testing of MCP as an organophosphate protective agent is warranted.

Cholinesterase Inhibitors↗

PubMed1992

Fat intake and clofibrate administration have interrelated effects on liver cholesterol concentration and serum butyryl cholinesterase activity in rats.

Rats were fed for 15 d purified diets with different amounts of coconut fat, and with or without clofibrate. Fat was added at the expense of an isoenergetic amount of glucose. The hypolipidemic action of clofibrate was not influenced by the amount of fat in the diet. Clofibrate did not affect liver cholesterol concentration in rats fed the low fat diet, but it counteracted the rise in liver cholesterol seen in rats fed the high fat diet. This could relate to the observed raised intestinal clofibrate-hydrolyzing activity of rats fed the high fat diet, because hydrolysis of clofibrate gives rise to its biologically active form. In rats fed the low fat diet, but not in those fed the high fat diet, clofibrate raised the activity of serum esterase-1, which (unlike esterase-2) does not hydrolyze clofibrate. Possibly, the dramatic stimulatory effect of fat feeding on serum esterase-1 activity had overruled any influence of clofibrate. Clofibrate elevated serum butyryl cholinesterase activity, with this effect being amplified by fat feeding. High levels of dietary fat in the absence of dietary clofibrate did not alter serum butyryl cholinesterase activity. Clofibrate did not change butyryl cholinesterase and esterase-1 activities in small intestine. The high fat diet caused slightly higher levels of butyryl cholinesterase activity in small intestine, but markedly raised intestinal esterase-1 activity. This study shows that certain effects of clofibrate and a high fat diet are interrelated.

Animals↗

PubMed1993

Noncholinergic functions of cholinesterases.

Cholinesterases (acetylcholinesterase and butyrylcholinesterase) exhibit additional catalytic activities apart from their well-known action in hydrolyzing choline esters. An amine-sensitive aryl acylamidase activity is exhibited by both acetyl- and butyrylcholinesterases. A metallocarboxypeptidase-like activity is found associated with both acetyl- and butyrylcholinesterases. The peptidase activity exhibited by butyrylcholinesterase was located in a 50-kDa COOH-terminal fragment. Acetylcholinesterase is implicated in noncholinergic functions in the substantia nigra. A relationship between tumorigenesis, cell differentiation, and cholinesterases has been speculated. The sequence similarities between different esterases, lipases, thyroglobulin, cell adhesion proteins, and cholinesterases would make it appear that cholinesterases are capable of exhibiting more than one biological activity and their functions are wider than what is hitherto known.

Acetylcholinesterase↗

PubMed1994

Antinociceptive effects of spinal cholinesterase inhibition and isobolographic analysis of the interaction with mu and alpha 2 receptor systems.

BACKGROUND: Spinal cholinergic receptors have been shown to have a potent antinociceptive action, an effect that can be mimicked by spinal cholinesterase inhibitors. We (1) characterized the cholinergic receptor system through which intrathecally applied cholinesterase inhibitors produce their antinociceptive effect and (2) examined their interaction with spinal mu opioid and alpha 2-adrenergic receptors. METHODS: Rats were prepared with chronic intrathecal catheters and the nociceptive threshold was assessed by the use of the radiant heat-evoked hind paw withdrawal. RESULTS: Spinal administration of neostigmine, edrophonium, carbachol, clonidine, and morphine produced a dose-dependent increase on the thermally evoked hind paw withdrawal latency. The order of potency (dose producing a 50% effect, in nanomoles) was morphine (1.1) = neostigmine (1.2) > clonidine (4.4) > carbachol (15) >> edrophonium (112). Spinal pretreatment with atropine (35 nmol) attenuated the antinociceptive effect of intrathecal carbachol (55 nmol), neostigmine (15 nmol), and edrophonium (500 nmol) but did not affect the potency of intrathecal morphine (15 nmol) or clonidine (435 nmol). In addition, intrathecal pretreatment with naloxone (31 nmol) and yohimbine (28 nmol) attenuated the effects of intrathecally administered morphine and clonidine, respectively, but did not significantly affect the potency of carbachol, neostigmine, or edrophonium. The nicotinic receptor antagonist mecamylamine (60 nmol) did not affect thermal nociception. Isobolographic analysis revealed a synergistic interaction after the coadministration of neostigmine-clonidine (P < 0.001), edrophonium-clonidine (P < 0.0001), and edrophonium-morphine (P < 0.01) mixtures. Neostigmine-morphine exhibited simple additivity. CONCLUSIONS: These data indicate that analgesia after spinal cholinesterase inhibition is mediated through muscarinic, but not nicotinic cholinergic, opioid, or alpha 2-adrenergic receptor systems, and that these spinal effects of cholinesterase inhibition interact synergistically with the antinociceptive effects of intrathecal mu and alpha 2 agonists.

Animals↗

PubMed1974

Cholinesterases from Plant Tissues: III. Distribution and Subcellular Localization in Phaseolus aureus Roxb.

The distribution and localization of cholinesterase in Phaseolus aureus, Glycine max, and Pisum sativum is described. The enzyme is present in roots, leaves, stems, root callus tissue, root cells suspension cultures, and root nodules. Cholinesterase in roots is found primarily in the cell wall. In cell fractionation experiments, at least 95% of the cholinesterase activity is associated with cell wall material. The enzyme can be solubilized by salt solutions, whereas Triton X-100 and sodium deoxycholate solubilize relatively small amounts of the enzyme. Cytochemical techniques have been employed to show the presence of cholinesterase activity at the cell surface and in the cell wall of certain cells of the root.

Journal Article↗

PubMed2003

Long-Term Cholinesterase Inhibitor Therapy for Alzheimer's Disease: Practical Considerations for the Primary Care Physician.

BACKGROUND: With the aging of the population, primary care physicians are increasingly expected to manage patients with Alzheimer's disease. For patients with this disease to obtain the best outcomes over the long term, early diagnosis and effective treatment are critical. Currently, cholinesterase inhibitors are the only drugs approved in the United States for the treatment of mild-to-moderate Alzheimer's disease. METHOD: Relevant clinical studies were identified through a search of the MEDLINE database using the terms Alzheimer's disease and donepezil, galantamine, or rivastigmine, using the limits of English language and publication dates of 1995 to 2003. Published studies were selected that provided information on the long-term use, defined as 1 year or longer, of second-generation cholinesterase inhibitors approved by the U.S. Food and Drug Administration for the treatment of mild-to-moderate Alzheimer's disease. RESULTS: 590 references were identified. Of these, 11 studies met the final study criteria, and 10 were selected (1 of the 11 was an interim analysis). CONCLUSIONS: The benefits of sustained long-term treatment with cholinesterase inhibitors have been demonstrated over the last several years. By reducing cognitive and functional decline over time, long-term cholinesterase inhibitor therapy enables patients to stay at home longer and may decrease the burdens faced by patients, caregivers, and society.

Journal Article↗

PubMed2000

[Localization, kinetic parameters, and functions of cholinesterase of the starfish ampulla].

The starfish amplullae cholinesterase was shown to represent acetylcholinesterase and enhance its activity along with increasing motility of the starfish. Bundles of muscle fibres containing cholinesterase were found in the ampullae. Cholinesterase was shown to be localized in the muscle cells and in collagen layer in vicinity of the muscle cells. The data obtained suggest participation of the starfish ampullae cholinesterase in non-synaptic cholinergic transmission between the radial nerve axons and the muscle fibre extension. Besides, the enzyme could take part in functional relationship between the muscle cells and the outer epithelial cells of the starfish ampullae.

Acetylcholinesterase↗

PubMed1976

Biological responsiveness to cholinesterase inhibition: a test for exploring the developmental maturity of the cholinergic system.

The acute mortality caused by two irreversible inhibitors of cholinesterases [diisopropylfluorophosphate (DFP) and diethoxyphosphorylthiocholine, 217 MI-phospholine iodide] has been investigated on chick embryos at different stages of development. The results demonstrate that the above compounds do not show any acute lethal action when administered before the 9th day of incubation; on the other hand, the administration is regularly followed by death after the 9th day of incubation. The doses are comparable to those causing death in hatched chicks. It has also been observed that no appreciable difference exists in DFP uptake from the yolk before and after the 9th day of incubation and that drug-induced cholinesterase inhibition is of the same order of magnitude at any developmental stage; the compound pyridine-2-aldoxime methanesulfonate (2-PAM) was a good antidote against DFP acute lethality. It seems likely that between the 8th and the 9th day of incubation the target system of organophosphorus inhibitors, that is, the cholinesterase enzymatic system, reaches a new point of maturation.

Animals↗

PubMed1999

Altered cholinesterase and monooxygenase levels in Daphnia magna and Chironomus riparius exposed to environmental pollutants.

Biochemical indices were investigated for their potential use as variables of sublethal toxicity in Daphnia (cholinesterase) and Chironomus (cholinesterase and biotransformation enzymes). Parathion, dichlorvos, and aldicarb caused dose-related inhibition of cholinesterase (ChE) in 24-h bioassays with both species. Ratios of Daphnia and Chironomus ChE IC50 values to corresponding immotility EC50 values derived from the same experiment covered the range 0.26 to 1.2. Estimates of the ChE inhibition caused by the immotility EC50 were in the range 53-99% below control activity. ChE IC50 values of dichlorvos, parathion, and aldicarb were 0.17, 0.61, and 95 microg/liter in Daphnia and 6.2, 2.9, and 27 microg/liter in Chironomus, respectively. Cytochrome P450-dependent monooxygenase activities (ethoxyresorufin-O-deethylase, methoxyresorufin-O-deethylase, and ethoxycoumarin-O-deethylase) were detectable in Chironomus but not in Daphnia. Chironomus monooxygenase activities were significantly inhibited to about 30% of control values after 4 days of exposure to 50 microg/liter 3, 4-dichloroaniline but remained unchanged by 0.5 microg/liter parathion. An approximately 1.3-fold induction of monooxygenase activities was caused by the model inducer naphthalene (0.1mg/liter). These results suggest that cytochrome P450-dependent monooxygenase activities may be useful variables in toxicity tests with aquatic insects.

Aldicarb↗

PubMed1987

Blood concentrations of 2,3-butanedione monoxime and some blood biochemical changes in Bubalus bubalis after intramuscular administration of this cholinesterase reactivator.

The blood levels of cholinesterase reactivator 2,3-butanedione monoxime were determined in buffalo calves following single intramuscular doses of 20 and 50 mg/kg body weight. Blood cholinesterases and other enzymatic activities were monitored at various times. The drug was rapidly absorbed with half-life of 0.09-0.12 h. The peak 2,3-butanedione monoxime blood concentrations of 24.7 +/- 0.3 and 38.9 +/- 1.7 micrograms/ml occurred at 10 min after 20 and 50 mg/kg doses, respectively. The elimination half-life varied between 3.05 +/- 0.12 and 3.80 +/- 0.19 h. Lack of adverse effect of 2,3-butanedione monoxime on blood cholinesterases and other enzymes indicated that intramuscular doses as high as 50 mg/kg may be safely employed in buffaloes.

Animals↗

PubMed1991

Structural and functional investigations of cholinesterases by means of affinity electrophoresis.

1. After a brief survey of the basic affinity electrophoresis concepts, the usual ways for preparing affinity electrophoresis ligands are examined. 2. Then results obtained on cholinesterases are reviewed. This section includes (a) structural and functional investigations on anionic sites, i.e., study of ligand-induced conformational change, organophosphate-induced "aging," genetic variants, and active-site topology; and (b) characterization of cholinesterase conjugates (hybrid proteins) and glycoinositol phospholipid-anchored cholinesterases. 3. The future prospects of affinity electrophoresis, e.g., investigations on the esteratic site and exploration of the carbohydrate moiety, are emphasized in the concluding section.

Affinity Labels↗

PubMed1996

Metrifonate induces cholinesterase inhibition exclusively via slow release of dichlorvos.

Metrifonate, a long-acting cholinesterase (ChE) inhibitor with very low toxicity in warm-blooded animals, inhibits rat brain and serum cholinesterase (ChE) in vitro through its hydrolytic degradation product, dichlorvos. This conclusion is based on the finding that metrifonate-induced ChE inhibition showed the same pH dependence as its reported dehydrochlorination to dichlorvos. The ChE inhibition induced by dichlorvos was not pH dependent. It was mediated by a competitive drug interaction with the catalytic site of the enzyme, which led to irreversible inhibition within several minutes of incubation. After this time, addition of further substrate to the inhibited enzyme was not able to promote drug dissociation and hence enzyme reactivation. Similar characteristics of inhibition, i.e. interaction with the substrate binding site and time-dependent switch to non-competitive inhibition were observed with the reference compound, physostigmine. However, the physostigmine-induced inhibition of ChE could be readily reversed by further substrate addition. Another reference compound, tetrahydroaminoacridine (THA), also induced a reversible inhibition of rat brain and serum cholinesterase, but with a mechanism of action different from that of both dichlorvos and physostigmine in that enzyme inhibition occurred rapidly upon drug addition at an allosteric site on the enzyme surface. It is suggested that the unique slow release plus the slow inhibition of ChE by dichlorvos is responsible for the lower toxicity of metrifonate compared to that of directly acting ChE inhibitors.

Animals↗

PubMed2006

Validation of an automated spectrophotometric assay for the determination of cholinesterase activity in canine serum.

The determination of enzymatic activity of cholinesterase is a useful diagnostic method to detect exposure to anticholinesterase compounds in human and in veterinary medicine. We validated a modification of the Ellman method in canine serum and applied it to the diagnosis of dogs poisoned with anticholinesterase substances. The method used butyrylthiocholine as substrate and potassium hexacyanoferrate as chromophore. The reference range calculated on 60 clinically healthy dogs was set between 3405 and 6561 U/L (chi-square test for normal distribution, p > 0.05). The overall mean intra-assay and inter-assay coefficients of variation were 0.53% and 3.83%, respectively. The assay was linear when using two sera with 12,538 U/L and 6604 U/L serum cholinesterase activity (r(2) = 0.997) and 0.999, respectively). The mean recovery values of pooled sera with a mean pseudocholinesterase (PChE) activity of 12,081 U/L and pooled sera with a mean PChE activity of 3415 U/L were 103.5% and 102.8%, respectively. Six dogs with a diagnosis of anticholinesterase compound intoxication showed a decrease in cholinesterase activity of at least 50% of normal activity with a mean +/- SD of 487 +/- 291 U/L ranging from 169 to 847 U/L. This technique conforms to the current standard for precision, linearity and accuracy and is a useful method for the complementary diagnosis of organophosphate or carbamate insecticide intoxication in dogs.

Animals↗