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)

The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated, however, the involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer's disease has not been as intensively considered. The limited ability of atypical antipsychotics to treat the cognitive impairment of schizophrenia, and cholinomimetics to treat the cognitive impairment of Alzheimer's disease, may be related to the influence of a multiplicity of neurotransmitter abnormalities including noradrenergic dysfunction, which these treatments do not address. The evidence of noradrenergic dysfunction occurring concomitantly with dopamine dysfunction in schizophrenia and acetylcholine dysfunction in Alzheimer's disease supports therapeutic approaches using noradrenergic drugs in combination with neuroleptics and cholinesterase inhibitors, respectively, to enhance the treatment of cognitive impairment. Given the results of animal and human studies, it appears that alpha-2A agonists may be the optimal choice for this purpose.
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PMID:The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. 1056 29

Comorbid schizophrenia and dementia is a common clinical phenomenon; however, management of the coexisting illnesses remains incomplete. Donepezil, a cholinesterase inhibitor, may be beneficial for the management of symptoms of Alzheimer's disease, a disease in which cholinergic pathways in the cerebral cortex and basal forebrain are well known to be compromised. Furthermore, impaired cognition in elderly schizophrenic patients has been observed to be more than two thirds; however, there are no published controlled studies reporting the use of cholinesterase inhibitors in the management of schizophrenia in patients with associated dementia. In this study, six patients with chronic schizophrenia and comorbid dementia were administered donepezil, 5 mg, in single-blind fashion as augmentation to their standard antipsychotic medication for a 4-week period. Patients were evaluated with the Mini Mental State Examination (MMSE); Alzheimer's Disease Assessment Scale, Cognitive subscale; Positive and Negative Symptom Scale (PANSS); and the Clinical Global Impression (CGI) scales. A significant improvement was noted in MMSE scores (P < 0.01) and for CGI scores (P < 0.01). In addition, three patients demonstrated improvement on the PANSS. Donepezil appears to be an effective treatment for the management of symptoms of dementia accompanying patients with comorbid schizophrenia and dementia. Since cholinergic dysfunction may be present in some patients with schizophrenia, the authors' findings further demonstrate the possibility that this disorder may be managed with cholinergic medications as augmenting agents, at least in this specific subpopulation of patients with comorbid dementia. To confirm the findings of this preliminary trial, further investigation is mandated with a larger sample of subjects in the context of a double-blind medication trial.
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PMID:Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia. 1256 59

It has been hypothesized that acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are coregulators of the duration of action of acetylcholine in cholinergic neurotransmission, suggesting that BuChE may also have an important role in the brain. To compare the expression of cholinesterases in the human thalamus, the distributions of BuChE and AChE activity were studied by using a modified Karnovsky-Roots method. BuChE activity was present mainly in neurons, whereas AChE activity was present in both neurons and axons. There was intense staining for BuChE or AChE throughout the thalamus, with some nuclei primarily expressing one or the other cholinesterase. BuChE staining was most intense and widespread in neurons in the anteroventral, mediodorsal, ventral, lateral, and pulvinar thalamic nuclei. AChE was predominantly expressed in neurons of the anterodorsal, midline, ventral, intralaminar, and reticular nuclei. Many nuclei contained both cholinesterases. Considering the overall patterns of labeling in the thalamus for the two cholinesterases, there were both complementary and overlapping relationships of BuChE and AChE activity. Neuronal staining in the subthalamic nucleus and hypothalamus was predominantly positive for AChE activity. The distinct distribution of BuChE activity in neurons in the human thalamus is consistent with an important role for this enzyme in neurotransmission in the human nervous system. Furthermore, BuChE activity, like AChE activity, is found in certain thalamic nuclei related to cognitive and behavioral functions. Involvement of thalamic nuclei in diseases of the nervous system such as Alzheimer's disease and schizophrenia suggests that BuChE could be a potential target for therapeutic intervention in these disorders.
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PMID:Differential distribution of butyrylcholinesterase and acetylcholinesterase in the human thalamus. 1281

We aimed to determine whether the cholinesterase inhibitor rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), would improve quality of life and cognitive function in 16 clinically stable subjects affected by schizophrenia in the residual phase. Study subjects began rivastigmine treatment at a dose of 1.5 mg bid. This dose was escalated at monthly intervals in increments of 1.5 mg bid to a maximum of 6 mg bid. All subjects were followed for 12 months. Quality of life was assessed using the Satisfaction with Life Domains Scale (SLDS, a self-report scale containing 10 "satisfaction" items); cognitive function, attentional function, and aspects of learning and memory were evaluated using common neuropsychological tests. Psychopathology was evaluated by means of the Brief Psychiatric Rating Scale (BPRS). Rivastigmine treatment resulted in significant improvements in quality of life, which were paralleled by significant improvements in cognitive function, learning and memory, and trends for improvement in attention. The BPRS factor "anergia" showed significant improvement, while low baseline scores in other psychotic factors did not permit further improvements. There were no reports of nausea or vomiting. In conclusion, rivastigmine significantly improved quality of life in subjects with schizophrenia. These benefits may relate to the drug's effects on cognitive deficits and negative symptoms associated with the condition.
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PMID:Effects of rivastigmine on cognitive function and quality of life in patients with schizophrenia. 1464 12

Increasing evidence suggests that the cholinergic system is involved in the pathogenesis of schizophrenia. Donepezil, a central cholinesterase inhibitor, improves psychotic symptomatology in demented patients, however, evidence for its role in the management of active psychosis in schizophrenia remains limited. An 18-week double blind cross-over study was conducted in which eight patients were randomly assigned to either donepezil (5 mg/day for the first 4 weeks and 10 mg/day for the following 4 weeks) or placebo as augmentation treatment to clozapine. After this initial phase, there was a 2-week washout period of the study medication after which the same regimen was crossed over at the same dose and for the same period (8 weeks). No significant difference was noted in the total positive and negative symptom scale scores when donepezil was compared with placebo (16.7%+12.97% vs 3.20%+13.94% respectively, p = 0.18). However, three patients improved (>15%) in the total PANSS scores (37.03%, 16.6% and 25.33%) during the donepezil treatment phase, while only one patient improved (20.87%) during the placebo phase. No differences were noted in the Calgary depression scale (p = 0.305), Simpson Angus scale (p = 0.374), clinical global impression-improvement scale (p = 0.23) and clinical global impression-severity of illness scores (p = 0.116). Although this preliminary study failed to demonstrate a clear effect of donepezil augmentation in clozapine treated chronic schizophrenia patients, it seems that the subtle positive effect of donepezil observed in some of our patients should encourage further investigation in a larger sample of this patient subpopulation.
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PMID:Donepezil augmentation of clozapine monotherapy in schizophrenia patients: a double blind cross-over study. 1525 26

Comorbid schizophrenia and dementia is becoming an increasingly common phenomenon. Because rivastigmine, a reversible acetylcholinesterase inhibitor, appears to delay the progression of Alzheimer's disease, it may also improve or delay the cognitive and behavioural disturbances evident in elderly chronic schizophrenia patients with comorbid cognitive decline. The aim of this study was to investigate augmentative rivastigmine administration in this population and to determine any effect on cognition, behaviour and 'activity of daily living' (ADLs) capabilities. Thirteen subjects with comorbid schizophrenia and dementia were administered open-label oral rivastigmine (9 mg/day) for a period of 12 weeks. The results indicated improvement in Mini-Mental State Examination scores (P<0.01), Alzheimer's Disease Assessment Scale-cognitive subscale scores (P<0.001), ADL scores (P<0.01) and Positive and Negative Syndrome Scale scores (P<0.01). Study observations indicate beneficial effects of rivastigmine administration in this subpopulation of schizophrenia patients. Following on from other studies of cholinesterase inhibitor agents, clinical improvement in this patient subpopulation may extend to the class of cholinesterase inhibitor agents in general and not necessarily be a specific effect of any of the medications. The effects noted may be specific to the subpopulation of comorbid schizophrenia and dementia rather than schizophrenia in general. Although speculative, these effects may be related to cholinergic dysfunction, which has been hypothesized to be present in some patients with schizophrenia.
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PMID:Rivastigmine augmentation in the management of chronic schizophrenia with comorbid dementia: an open-label study investigating effects on cognition, behaviour and activities of daily living. 1548 16

Cognitive impairment in schizophrenia occurs in the early phases of the disease and remains throughout its course. The basis for cognition lies in two main brain regions: the prefrontal cortex and hippocampus. Positron emission tomography, functional magnetic resonance imaging, and proton magnetic spectroscopy studies have shown that prefrontal cortex and hippocampus activity and cell density are lower in patients with schizophrenia than in healthy controls. Dopamine remains the fundamental neurotransmitter involved with schizophrenia. Catechol- O -methyltransferase accounts for about 60% of dopamine metabolism in the prefrontal cortex. Functional polymorphism for the catechol- O -methyltransferase genotypes has been identified in patients with schizophrenia. Those with the valine-valine genotype demonstrate rapid inactivation of dopamine, and performance in cognitive testing in patients is poorer with this allele than with other genotypes. N -methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate acid receptors are also strongly associated with cognitive impairment. Changes occur in apolipoproteins D and E, cholinesterase enzyme activity, neurotensin, and neural growth factors, leading to a possible neurodegenerative process and cognitive impairment in patients with schizophrenia. A fundamental link between psychosis and neurocognition probably arises from complex interactions between these systems at the intracellular secondary messenger system and with protein phosphorylation. Atypical antipsychotics evaluated in receptor models, cell cultures, and animal behavior paradigms indicate that these agents may provide neuroprotective effects. Clinical studies with atypical antipsychotics have consistently demonstrated improvement in cognitive symptoms, and such improvement appears to be correlated with improvement of negative symptoms. A neurodevelopmental model of cognitive impairment in schizophrenia aids in understanding why atypical antipsychotics improve cognitive symptoms.
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PMID:Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis. 1558 43

The effect of lovastatin and thioridazine on the degradation of cocaine in human serum was studied by incubating therapeutic and toxic concentrations of either drug with cocaine in human serum at 37 degrees C. Without these other drugs, cocaine concentrations decreased by an average of 88% in 120 minutes. Lovastatin at all concentrations studied showed a negligible effect on the degradation of cocaine in human serum and did not alter the pseudocholinesterase activity of the serum. In contrast, in the presence of a therapeutic concentration of thioridazine, cocaine concentrations decreased by only 71% during this period of time, and, with a toxic concentration of thioridazine, cocaine concentrations decreased by only 55%. Thioridazine suppressed the pseudocholinesterase activity of human serum by up to 19% during the 120-minute incubation period, and this effect was more pronounced at higher thioridazine concentrations. These findings suggest that thioridazine may prolong the serum half-life of cocaine by inhibiting the pseudocholinesterase-mediated catabolism of cocaine to ecgonine methyl ester. This may be important in cocaine users who are treated with phenothiazines and other structurally similar drugs. They also may be of interest in cocaine-abusing patients who are treated with phenothiazines for schizophrenic disorders.
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PMID:The effect of lovastatin and thioridazine on the degradation of cocaine in human serum in vitro. 1579 47

This study assessed the neural correlates of the effects of rivastigmine, a CNS-selective cholinesterase inhibitor, given as an add-on therapy to antipsychotics-treated patients with schizophrenia who displayed moderate cognitive impairments, using functional magnetic resonance imaging (fMRI) during a sustained attention task. The study used a placebo-controlled, randomized, double-blind longitudinal design. Twenty patients stable on antipsychotics, 11 assigned to receive rivastigmine and 9 to receive placebo, underwent fMRI and clinical assessments at baseline and after 12 weeks. The fMRI task used a periodic block design and involved 3 conditions: rest, detecting a nonzero number ("nonzero" condition), and detecting a specific number ("specific number" condition) among a series of 6-digit numbers. Online data (via button presses) were acquired on both occasions. Behavioral results showed a trend (P = 0.075) for the rivastigmine-treated patients to have more correct responses and the placebo group to have fewer correct responses at 12 weeks compared with baseline in the "nonzero" condition. There was also an increase in regional brain activity in the cerebellum in the rivastigmine group at 12 weeks in both conditions, which was only partially explained by change in behavioral measures; no change was observed in the placebo group. Our results showed that rivastigmine treatment increased cerebellar activity and influenced attentional processes.
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PMID:Effects of rivastigmine on sustained attention in schizophrenia: an FMRI study. 1601 72

Social withdrawal is the first sign and key component of the negative symptoms of schizophrenia. The efficacy of risperidone, an atypical antipsychotic, on the symptom is practically limited by dose-dependent side effects in clinical trials, therefore there is the need for adjuvant treatments. In the present study, we aimed to investigate the synergistic effect and mechanism of risperidone and galantamine, which is a nicotinic acetylcholine receptor (nAChR)-allosteric modulator and a modest cholinesterase inhibitor, on phencyclidine (PCP)-treated mouse model of social withdrawal. At non-effective doses by themselves, co-administration of galantamine (0.05mg/kg) and risperidone (0.05mg/kg) showed synergistic effects on PCP-induced impairments of social interaction and dopamine release in the medial prefrontal cortex (mPFC). The behavioral synergistic effect was abolished by the administration of a dopamine-D(1) receptor antagonist, SCH 23390 (0.02mg/kg, systemic; or 0.02microg/0.5microL/mouse, intra-mPFC), and a nAChR antagonist, mecamylamine (3mg/kg), but not a muscarinic receptor antagonist, scopolamine (0.1mg/kg). Mecamylamine (3mg/kg) also abolished the synergistic effect on dopamine release in the mPFC. We conclude that galantamine may have synergistic effect with risperidone on the negative symptom of social withdrawal in schizophrenia, which is mediated by dopamine-D(1) receptors in the mPFC through nAChR activation-increased dopamine release.
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PMID:Synergistic effect of galantamine with risperidone on impairment of social interaction in phencyclidine-treated mice as a schizophrenic animal model. 1731 62


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