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)

Therapeutic strategies aimed to treat Alzheimer's disease (AD) may either produce an attenuation of symptoms or slowdown deterioration by attenuating progression of the disease. Presently, cholinesterase inhibitors (ChEI) have shown the most promising therapeutic effects. The best documented clinical efficacy of ChEI are studies of THA (tacrine, tetrahydroaminoacridine). The results of five recent studies in a total of 1,242 patients are discussed. Based on differences from placebo in scoring, a gain of 2-12 (MMSE) or 5-6 (ADAS) in deterioration can be seen for a THA treatment of 2-3 mo duration. This suggests that if treatment with THA will be extended to a longer period, the drug effect may not be only a symptomatic improvement but also a slowdown of disease course. A similarity of THA's effect in AD with L-deprenyl effects in Parkinson's is suggested.
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PMID:Therapy for Alzheimer's disease. Symptomatic or neuroprotective? 788 87

A placebo-controlled cross-over trial (n = 89) investigated the use of a chronic dose of the cholinesterase inhibitor THA, as a treatment for dementia of the Alzheimer type (DAT). Effects on both subjective clinical rating scales and objective computerised tests were assessed. In regard to the former, analysis of the three main clinical outcome measures showed statistically significant effects of the drug on the Mini-Mental State Examination (MMSE) and the Abbreviated Mental Test Score (AMTS), but not on the Activities of Daily Living scale (ADL). Using the objective computerised CANTAB tests, sensitive to specific aspects of memory and attention, evidence was found for improvements in attentional function rather than memory, in patients with mild to moderate DAT. Although these improvements were significant, they were small and restricted to certain tests of attentional function. Nevertheless, they add to the growing body of evidence that the cholinergic system is involved in the control of attentional processes; and are substantiated by the findings of a second study examining the effects of an acute dose of nicotine on attentional and mnemonic performance in patients with DAT. This study found significant improvements in cognitive performance in patients receiving nicotine, in objective tests of attention but not of short-term memory. These data will clearly provide important comparative data for future investigations of putative cognitive enhancing drugs in DAT sufferers.
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PMID:Tetrahydroaminoacridine (THA) in Alzheimer's disease: an assessment of attentional and mnemonic function using CANTAB. 812 35

The anticholinesterase properties of tetrahydroaminoacridine (THA, Tacrine), alpha-tocopheryl hemisuccinate (TS), and cholesteryl hemisuccinate (CS), given alone and in combination, were examined in vitro. Results from these studies indicate that: [1] THA is a potent inhibitor of acetylcholinesterase (AChE, IC50 of 0.40 microM) and butyrylcholinesterase (BChE, IC50 of 0.10 microM) with greatest inhibitory activity towards BChE; [2] TS and CS are weak inhibitors of BChE (IC50 of 100 microM and 168 microM, respectively) but potent inhibitors of ACHE (IC50 of 1.73 microM and 0.79 microM, respectively); [3] both TS and CS treatment in combination with THA significantly increased THA's anticholinesterase activity. The percentage AChE inhibition observed with this combination was often significantly greater than the sum of the individual values (synergistic). The addition of 0.5 microM CS or TS to an ACHE preparation reduced THA's IC50 value from 0.40 microM or 0.18 microM, respectively [4]; inhibition of AChE by THA, TS and CS are mixed non-competitive while THA inhibition of BChE is mixed non-competitive and TS and CS inhibition of BChE are simple non-competitive; and [5] inhibition of cholinesterases by TS and CS occurs immediately (50 to 75%), during the first 30 min of incubation (25 to 50%) and is dependent on the anionic charged portion of the molecule. In conclusion, our experimental data indicate that TS and CS are potent inhibitors of AChE activity and significantly potentiate the anticholinesterase activity of THA. Such potent and synergistic inhibition of AChE suggest that TS or CS, alone and in combination with THA, may prove beneficial in the treatment of organophosphate poisoning and Alzheimer's disease.
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PMID:Inhibition of cholinesterase activity by tetrahydroaminoacridine and the hemisuccinate esters of tocopherol and cholesterol. 818 46

The present study compares the effects of two cholinesterase inhibitors, tetrahydroaminoacridine (THA, 1 and 3 mg/kg) and physostigmine (0.12 and 0.36 mg/kg), on spatial navigation (water maze, WM) and avoidance (step through passive avoidance, PA) performance. THA and physostigmine did not facilitate WM or PA performance in control or p-chlorophenylalanine (PCPA)-treated rats. THA at 3 mg/kg, but not at 1 mg/kg, completely restored the defect in WM and PA performance in rats pretreated with 7.5 mg/kg mecamylamine, a centrally active nicotinic antagonist. Physostigmine completely restored behavior in WM and PA tests at 0.12 and 0.36 mg/kg in mecamylamine-treated rats. In rats pretreated with mecamylamine+PCPA, 3 mg/kg THA to some extent restored WM performance but had no effect on PA retention. Likewise, physostigmine partially restored WM performance but did not facilitate PA retention in mecamylamine+PCPA-pretreated rats. The present study suggests that serotonergic dysfunction may decrease the efficacy of cholinesterase inhibitors to reverse the defect in WM and PA behavior occurring as a consequence of a decrease in activity of nicotinic-mediated functions.
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PMID:Effects of THA and physostigmine on spatial navigation and avoidance performance in mecamylamine and PCPA-treated rats. 830 18

Using a three-panel runway task, the effects of NIK-247 on impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia were investigated in rats; these effects were compared with those of the well-known cholinesterase inhibitors, tetrahydroaminoacridine (THA) and physostigmine. Intraperitoneal injection of scopolamine (0.56 mg/kg) significantly increased the number of errors (pushes made on the two incorrect panels of the three-panel gates located at four choice points). NIK-247 (3.2-18 mg/kg PO), THA (1-10 mg/kg PO), and physostigmine (0.1 and 0.32 mg/kg IP) dose-dependently reduced the increase in errors induced by scopolamine. NIK-247 (32 mg/kg) was also effective in reducing the increase in errors produced by lesions of the dorsal hippocampus. A 5-min period of cerebral ischemia markedly increased the number of errors. NIK-247 (3.2 and 10 mg/kg), given immediately after blood flow recirculation and again 20 min before the runway test carried out 24 h after ischemia, significantly reduced the increase in errors expected to occur after ischemia. Tetrahydroaminoacridine (3.2 mg/kg) and physostigmine (0.1 mg/kg) similarly reversed the increased errors in ischemic rats. These results suggest that NIK-247 alleviates the impairment of working memory produced by scopolamine, hippocampal lesions, and cerebral ischemia, possibly through activation of the central cholinergic system.
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PMID:Ameliorative effects of the centrally active cholinesterase inhibitor, NIK-247, on impairment of working memory in rats. 843 69

1,2,3,4-Tetrahydro-9-aminoacridine (THA, tacrine) is a potent cholinesterase (ChE) inhibitor which is under consideration for the treatment of Alzheimer's disease. This paper examines the effect of in vivo microdialysis of THA, THB-013 (an analog of THA) and physostigmine on the extracellular concentration of acetylcholine (ACh) in the striatum of anesthetized rat, as well as their effects on in vitro striatal ChE activity. In addition, the interaction of THA and physostigmine with cholinergic receptors in rat striatum has been investigated. All three drugs inhibited ChE activity and increased the extracellular concentration of ACh in a concentration-dependent manner. In the presence of THA, atropine induced a smaller increase in extracellular ACh concentrations than it did in the presence of physostigmine, under experimental conditions in which THA (100 microM) and physostigmine (10 microM) produced an equivalent effect on ChE activity. THA bound significantly to both muscarinic and nicotinic receptors in rat striatum, whereas physostigmine did not show significant binding. THA (100 microM) and physostigmine (10 microM) produced an additive effect on the extracellular concentration of ACh, and the addition of THA (10 microM) to physostigmine (1 microM) produced further inhibition of in vitro ChE activity. 4-Aminopyridine (100 microM), a K+ channel blocker, showed no detectable effect by itself on the extracellular concentration of ACh, however, it significantly increased the extracellular concentration of ACh in the presence of physostigmine (10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of in vivo microdialysis of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on the extracellular concentration of acetylcholine in the striatum of anesthetized rats. 849 22

The present study investigated the impact of the cholinesterase inhibitor tetrahydroaminoacridine (THA; tacrine) on sleep in healthy subjects. According to the reciprocal interaction model of non-rapid eye movement (NREM) and REM sleep regulation, which postulates a primary role in cholinergic neurotransmission for the initiation and maintenance of REM sleep, it was expected that THA would lead to an earlier onset of REM sleep. In 12 healthy subjects aged from 21 to 50 years two different doses (20 mg, 40 mg) were administered 1 hour prior to bed time and compared to placebo. Only the higher dose of THA significantly shortened REM latency. No other significant effects on sleep architecture were observed, although administration of 40 mg tacrine was associated with a decrease in sleep efficiency and a prolongation of sleep latency. Blood plasma levels of tacrine and its metabolite 1-hydroxytacrine measured prior to sleep and during the first 90 min of sleep were significantly correlated with the onset of REM sleep in relation to the timing of drug administration (only for the 20 mg dose). The reversible cholinesterase inhibitor THA exerts effects on REM latency comparable to those observed with other cholinomimetic agents.
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PMID:Effect of tetrahydroaminoacridine on sleep in healthy subjects. 873 20

Following the introduction of tacrine hydrochloride (Cognex) in the United States and several other countries, researchers are pursuing two broad therapeutic strategies for Alzheimer's disease (AD). The first involves identifying agents or combinations of agents whose actions can compensate for the considerable cerebral damage that has typically occurred by the time the diagnosis of AD is made. Such therapeutic approaches include the development of additional cholinesterase inhibitors, agents that work on the receptors of other systems damaged by the disease process, and anti-inflammatory and immunomodulatory agents. The second and ultimately more promising strategy involves the development of approaches to retard, halt, or even prevent disease progression. Such protective approaches, which depend on the development of more effective methods for predicting and diagnosing AD, include the administration of nerve growth factor and other neurotrophins and the use of pharmacologic or genetic interventions to limit amyloid deposition and the formation of neurofibrillary tangles.
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PMID:Treatment of Alzheimer's disease: future directions. 874 Oct

We investigated the ability of a cholinesterase inhibitor, metrifonate, to desynchronize cortical EEG activity. Metrifonate suppressed immobility-related high voltage spindling activity in young and aged rats at doses of 30 and 60 mg kg-1, p.o., and 10, 30 and 60 mg kg-1, p.o., respectively. The increase in EEG 1-20 Hz amplitude induced by scopolamine (0.2 mg kg-1, i.p.) was fully alleviated by metrifonate (30 and 100 mg kg-1, p.o.) and partially alleviated by a reference cholinesterase inhibitor, THA (3 and 6 mg kg-1, i.p.). Nucleus basalis (NB) lesions induced by quisqualic acid decreased frontal cortical choline acetyltransferase activity by 80% and increased cortical EEG slow waves. Metrifonate and THA did not reverse NB lesion-induced EEG abnormality. We conclude that metrifonate enhances cholinergic desynchronization of cortical EEG waves and that a severe defect of presynaptic NB cholinergic fibres limits the therapeutic effects of metrifonate.
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PMID:An indirect cholinesterase inhibitor, metrifonate, increases neocortical EEG arousal in rats. 880 59

Substantial evidences suggest that the increased cerebral deposition, and neurotoxic action of the beta-amyloid peptide, the major constituent of senile plaques, may represent the underlying cause of the cognitive deficits observed in Alzheimer's disease. Herein, we attempted to verify this hypothesis by inducing a potential Alzheimer's-type amnesia after direct intracerebroventricular administration of aggregated beta 25-35-amyloid peptide in mice. In this aim, mnesic capacities were evaluated after 6-13 days, using spontaneous alternation in the Y-maze, step-down type passive avoidance and place learning in a water-maze. Pretraining administration of aggregated beta 25-35 peptide induced dose-dependent decreases in both alternation behaviour and passive avoidance, at doses of 3 and 9 nmol/mouse. A reduced but still significant impairment was observed when the peptide was not aggregated, or 'aged', by preincubation for 4 days at 37 degrees C. The beta 1-28 peptide, at 3 nmol/mouse, also induced a marked decrease in step-down latency. Posttraining, but not preretention, administration of beta 25-35 peptide also significantly impaired learning. The beneficial effects of cholinergic agents on beta 25-35-induced amnesia was examined using the cholinesterase inhibitor tacrine (THA, 1.3 and 4.3 mumol/kg i.p.) and the nicotinic receptor agonist (-)-nicotine (NIC, 0.06 and 0.2 mumol/kg i.p.). Both drugs induced a dose-dependent abrogation of the beta 25-35-induced decreases in alternation behaviour and passive avoidance. Furthermore, THA, at 1.3 mumol/kg, and NIC, at 0.2 mumol/kg, also reversed the beta 25-35-induced impairment of place learning and retention in the water-maze. Histological examination of Cresyl violet-stained brain sections indicated a moderate but significant cell loss within the frontoparietal cortex and the hippocampal formation of mice treated with aged beta 25-35 peptide (9 nmol). Examination of Congo red-stained sections in the same animals demonstrated the presence of numerous amyloid deposits throughout these brain areas. These results confirm that the deposition of beta-amyloid peptide in the brain is in some way related to impairment of learning and cholinergic degeneration and suggest that the [25-35] fragment of the beta-amyloid protein, sufficient to induce neuronal death in cultures, also induces an Alzheimer's-type amnesia in mice.
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PMID:Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. 882 55


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