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)

We have previously reported that long-term treatment with clarithromycin (CAM) increased the median survival of patients with non-small cell lung cancer, and improved various clinical parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer, who had received chemotherapy, radiotherapy or both (basic cancer therapy). Patients with clinical backgrounds matched to the CAM group, who did not receive CAM treatment, were included into this study as a control group (non-CAM group). CAM treatment was initiated 4 weeks after the basic cancer therapy. The non-CAM group did not receive a placebo. Before and after the 3-month treatment with CAM, body weight, serum levels of interleukin-6 (IL-6, a cytokine which, together with TNF-alpha, plays a crucial role in the development of cancer cachexia), total protein, albumin, cholinesterase and hemoglobin were measured for the evaluation of the patients' clinical status. There were no statistically significant differences in serum levels of IL-6 between the CAM group before the treatment and the non-CAM group. After 3 months of CAM treatment, serum levels of IL-6 significantly decreased. In contrast, body weight, cholinesterase, and hemoglobin increased to a significant extent. Among these four parameters, however, the decrease in serum IL-6 levels was only statistically correlated with the increase in body weight, but not with that in other parameters. Furthermore, CAM-treated patients whose serum IL-6 levels were decreased after 3 months of treatment survived longer: there was a statistically significant correlation between the decrease in serum IL-6 and survival time. In contrast, in the non-CAM group, these parameters did not change significantly during the study. These results suggest that CAM may reduce the progression of cancer-associated cachexia.
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PMID:Anti-cachectic effect of clarithromycin for patients with unresectable non-small cell lung cancer. 1178 60

Exposure to an open field is psychologically stressful and leads to an elevation in core temperature (T(c)). Methyl scopolamine (MS), a muscarinic antagonist, and pyridostigmine (PYR), a carbamate that inhibits acetylcholinesterase, do not cross the blood-brain barrier and have little effect on T(c) in resting, nonstressed animals. However, we have found that MS has an antipyretic effect on T(c) that is caused by handling and cage-switch stress. PYR should act pharmacologically to reverse the effects of MS. To this end, we assessed the effects of MS and PYR on stress-induced hyperthermia. Male Sprague-Dawley rats at 90 days of age were housed individually at an ambient temperature of 22 degrees C. T(c) and motor activity were monitored by radiotelemetry in an open-field chamber. Rats were dosed intraperitoneally at 1200 with 1.0 mg/kg MS, 0.1 mg/kg PYR, a combination of MS and PYR, or saline and placed immediately inside the open-field chamber for 60 min. Stress-induced hyperthermia was suppressed immediately by MS and enhanced by PYR. T(c) only increased by 0.3 degrees C in the MS-treated animals. The hyperthermic response in the PYR group was nearly 0.6 degrees C above that of rats dosed with saline. Coadministration of PYR and MS led to a stress-induced hyperthermia response nearly identical to that of rats injected with saline. Overall, open-field stress exacerbated the effects of MS and PYR on body T(c) and provides support for a peripheral cholinergic mechanism that mediates stress-induced hyperthermia.
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PMID:Peripheral cholinergic pathway modulates hyperthermia induced by stress in rats exposed to open-field stress. 1179 93

The present study assessed the effects of repeated subacute exposure to the organophosphorous nerve agent, sarin. Guinea pigs were injected five times per week (Monday-Friday) for 2 weeks with fractions of the established LD(50) dose of sarin (42 microg/kg sc). The animals were assessed for the development of cortical EEG seizures. Changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels and neurobehavioral reactions to a functional observational battery were monitored over the 2 weeks of sarin exposure and for an extended postinjection period. There were dose-related changes in body weight and RBC AChE levels. No guinea pigs receiving 0.3, 0.4 or 0.5 x LD(50) of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline. Seizures were evident in animals receiving 0.6 x LD(50) of sarin as early as the second day, and subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD(50) sarin showed obvious signs of cholinergic toxicity, which included a significant increase in their angle of gait. Overall, 2/13 animals receiving 0.5 x LD(50) sarin died before all 10 injections were given. By the 10th day of injections, the animals receiving saline were significantly easier to remove from their cages and handle as compared to the first day of injections. They were also significantly less responsive to an approaching pencil and touch on the rump in comparison to the first day of testing. In contrast, the animals receiving 0.4 x LD(50) sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared to the first day. The 0.5 x LD(50) sarin animals failed to show any significant changes to the approach response and touch response and did not adjust to handling or cage removal from the first day of injections to the last day of handling. In summary, the guinea pigs receiving the 0.4 x LD(50) and 0.5 x LD(50) doses of sarin failed to habituate to some aspects of the functional observational battery testing.
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PMID:The dose-response effects of repeated subacute sarin exposure on guinea pigs. 1206 73

Adult male Long-Evans rats were subjected to bilateral lesions of the cholinergic neurons in the nucleus basalis magnocellularis (NBM) by injection of 0.2 or 0.4 microg 192-IgG-saporin in 0.4 microl phosphate-buffered saline. Control rats received an equivalent amount of phosphate-buffered saline. Starting 2 weeks after surgery, all rats were tested for locomotor activity in their home cage, beam-walking performance, T-maze alternation rates (working memory), reference and working memory performance in a water-maze task, and memory capabilities in the eight-arm radial maze task using uninterrupted and interrupted (delay of 2 min, 2 h and 6 h after four arms had been visited) testing procedures. Histochemical analysis showed a significant decrease of acetylcholinesterase (AChE)-positive reaction products (30-66%) in various cortical regions at the 0.2-microg dose. At the dose of 0.4 microg, there was an additional, although weak, damage to the hippocampus (17-30%) and the cingulate cortex (34%). The behavioral results showed only minor impairments in spatial memory tasks, and only during initial phases of the tests (reference memory in the water maze, working memory in the radial maze). The behavioral effects of the dramatic cholinergic lesions do not support the idea of a substantial implication of cholinergic projections from the NBM to the cortex in the memory processes assessed in this study, but they remain congruent with an involvement of these projections in attentional functions.
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PMID:Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats. 1217 91

Pyridostigmine is a short-acting inhibitor of cholinesterase (ChE) used as a pretreatment against potential nerve agent exposure during the Persian Gulf War. As pyridostigmine contains a quaternary ammonium group, it is generally believed to elicit changes in the peripheral nervous system function only. It has been hypothesized, however, that the neurotoxicity of pyridostigmine may be altered by either stress or combined exposures to other toxicants. We evaluated the effects of forced running stress, exposure to the organophosphate anticholinesterase paraoxon, or a combination of both on the acute neurotoxicity of pyridostigmine. ChE (blood, diaphragm, and selected brain regions) and carboxylesterase (CE; liver, plasma) inhibition was also evaluated. Young adult male Sprague-Dawley rats were either given vehicle or paraoxon (0.1 mg/kg, i.m.) and subsets placed in their home cage or forced to run on a treadmill for 60 min. Pyridostigmine (0, 10 or 30 mg/kg, p.o.) was given 60 min after paraoxon dosing and rats were evaluated for cholinergic toxicity just prior to sacrifice 60 min later. No signs of toxicity were noted following paraoxon exposure while both dosages of pyridostigmine (10 and 30 mg/kg, p.o.) elicited signs of functional toxicity. Toxicity was not different with combined paraoxon-pyridostigmine exposures and forced running did not influence toxicity under any conditions. Paraoxon (0.1 mg/kg, i.m.) caused moderate (23-46%) ChE inhibition in blood, diaphragm and brain 2 h after exposure. Pyridostigmine (10 or 30 mg/kg, p.o.) caused extensive inhibition of blood (88-94%) and diaphragm (75-85%) ChE activity but no significant effect on brain regional ChE activity. Forced running stress did not influence the degree of tissue ChE inhibition following either paraoxon, pyridostigmine or paraoxon-pyridostigmine combined exposures. CE activities were inhibited (26-43%) in plasma and liver by paraoxon but inhibition was not influenced by either stress or combined paraoxon-pyridostigmine exposures. These results suggest that subclinical paraoxon exposure and forced running stress, by themselves or in combination, have little effect on acute pyridostigmine toxicity in rats.
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PMID:Combined forced running stress and subclinical paraoxon exposure have little effect on pyridostigmine-induced acute toxicity in rats. 1292 76

Cage amines 1-4 are potent peripheral anionic site-bound reversible inhibitors of both acetylcholinesterase and butyrylcholinesterase. Cage amines 1-3 are selective butyrylcholinesterase inhibitor versus acetylcholinesterase. For both enzymes, the -log K(i) values linearly correlate with the difference of substituted phenyl radius of cage amines (-log K(i)=5.4+3.4Deltagamma for acetylcholinesterase, -log K(i)=5.9+3.2Deltagamma for butyrylcholinesterase). Moreover, the relationship between the enzymes and cage amines mimics that between bottles and stoppers.
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PMID:Cage amines as the stopper inhibitors of cholinesterases. 1461 50

Adult Long-Evans male rats were subjected to electrolytic lesions of the ventral subiculum, and tested for locomotor activity in the home cage, reference and working memory in the water maze, working memory in the radial maze, and D-amphetamine-induced locomotion (1mg/kg, i.p.). When compared to their sham-operated counterparts, lesioned rats showed nocturnal hyperactivity, no reference memory deficit, but working memory was impaired in the water maze and during the initial stage of radial-maze testing. Their locomotor responsiveness to D-amphetamine was exaggerated. Histological verifications confirmed lesions in the ventral subiculum. Material stained for acetylcholinesterase activity indicated septohippocampal and commissural/associational sprouting, accounting for partial damage to the perforant paths. These results showed that ventral subiculum lesions (i) do not alter the capability of rats to learn repeatedly presented spatial information, and (ii) impair, but do not prevent, spatial working memory, suggesting that the ventral subiculum is preferentially involved in short-term memory for spatial locations. Given the electrolytic nature of the lesion, the lesion-induced potentiation of the locomotor response to amphetamine is probably easier explained by partial disruption of the perforant paths than by damage to neurons of the ventral subiculum.
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PMID:Electrolytic lesions of the ventral subiculum weakly alter spatial memory but potentiate amphetamine-induced locomotion. 1513 66

Lambert-Eaton myasthenic syndrome (LEMS) is an idiopathic or paraneoplastic syndrome producing antibodies against presynaptic voltage-gated P/Q calcium channels. This decreases calcium entry into the presynaptic terminal, which prevents binding of vesicles to the presynaptic membrane and acetylcholine release. LEMS is most often associated with small cell lung cancer, although idiopathic presentations comprise approximately 40% of the cases. The most common initial complaint is proximal muscle weakness involving the lower extremities more than the upper extremities. Depressed deep tendon reflexes and autonomic dysfunction are frequently present. Involvement of the bulbar or respiratory muscles is rare. Diagnosis is confirmed by electrophysiological testing, which demonstrates small compound muscle action potentials and facilitation with exercise or 20-Hz repetitive stimulation. A serum test for voltage-gated calcium channel antibodies is commercially available. Treatment involves removing the cancer associated with the disease. If cancer is not found, immunosuppressive medications and acetylcholinesterase inhibitors are used with moderate success. Patients with idiopathic LEMS should be screened every 6 months with chest imaging for cancer.
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PMID:Lambert-Eaton myasthenic syndrome. 1525 11

This project assessed the effects of repeated low-dose exposure of guinea pigs to the organophosphorus nerve agent sarin. Animals were injected once a day, 5 days per week (Monday-Friday), for 2 weeks with fractions (0.3x, 0.4x, 0.5x, or 0.6x) of the established LD(50) dose of sarin (42 microg/kg, s.c.). The animals were assessed for changes in body weight, red blood cell (RBC) acetylcholinesterase (AChE) levels, neurobehavioral reactions to a functional observational battery (FOB), cortical electroencephalographic (EEG) power spectrum, and intrinsic acetylcholine (ACh) neurotransmitter (NT) regulation over the 2 weeks of sarin exposure and for up to 12 days postinjection. No guinea pig receiving 0.3, 0.4 or 0.5 x LD(50) of sarin showed signs of cortical EEG seizures despite decreases in RBC AChE levels to as low as 10% of baseline, while seizures were evident in animals receiving 0.6 x LD(50) of sarin as early as the second day; subsequent injections led to incapacitation and death. Animals receiving 0.5 x LD(50) sarin showed obvious signs of cholinergic toxicity; overall, 2 of 13 animals receiving 0.5 x LD(50) sarin died before all 10 injections were given, and there was a significant increase in the angle of gait in the animals that lived. By the 10th day of injection, the animals receiving saline were significantly easier to remove from their cages and handle and significantly less responsive to an approaching pencil and touch on the rump in comparison with the first day of testing. In contrast, the animals receiving 0.4 x LD(50) sarin failed to show any significant reductions in their responses to an approaching pencil and a touch on the rump as compared with the first day. The 0.5 x LD(50) sarin animals also failed to show any significant changes to the approach and touch responses and did not adjust to handling or removal from the cage from the first day of injections to the last day of handling. Thus, the guinea pigs receiving the 0.4 and 0.5 x LD(50) doses of sarin failed to habituate to some aspects of neurobehavioral testing. Spectral analysis of EEG data suggested that repeated sarin exposure may disrupt normal sleeping patterns (i.e., lower frequency bandwidths). While these EEG changes returned to relative normalcy 6 days after the last injection in animals receiving 0.4 x LD(50) sarin, these changes were still observed in the animals that received 0.5 x LD(50) sarin. Ten to twelve days after the last sarin injection (in 0.4 x LD(50) group only), neurochemical data showed that striatal choline levels were reduced in comparison to the saline group. At this time, atropine sulfate (5 mg/kg, i.p.) challenge resulted in a transient elevation in striatal ACh levels in animals exposed to repeated 0.4 x LD(50) sarin as well as in control animals. No evidence of brain or heart pathology was found in any guinea pig that survived all 10 sarin injections.
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PMID:The effects of repeated low-dose sarin exposure. 1655 54

The nucleus accumbens may play a role in acquisition and expression of behavioral depression as measured using the inescapable swim test. Previous work shows that a local injection of a cholinergic muscarinic-1 receptor agonist increases immobility and a specific muscarinic-1 antagonist acts as an antidepressant-like drug by increasing swimming escape efforts. The present study used microdialysis to monitor extracellular acetylcholine levels in the accumbens, fluorescent labeled toxins to monitor changes in acetylcholinesterase and muscarinic-1 receptors, and semiquantitative-polymerase chain reaction to detect changes in gene expression for the muscarinic-1 receptor. Microdialysis showed that acetylcholine levels did not change while an animal was swimming; however, a significant transient decrease occurred when the rat was returned to the dialysis cage, followed by a long-lasting increase that reached a maximum three hours after the test. Acetylcholine levels stayed high even 24 h after the initial test as evidenced by a significant elevation in basal level prior to the second swim. This increase in neurotransmitter may have been partially compensated by a significant increase in the degradative enzyme, acetylcholinesterase, and by a decrease in muscarinic-1 receptors and their gene expression. These results further demonstrate the importance of accumbens cholinergic function in the appearance of a depression-like state.
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PMID:Behavioral depression in the swim test causes a biphasic, long-lasting change in accumbens acetylcholine release, with partial compensation by acetylcholinesterase and muscarinic-1 receptors. 1667 71


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