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)

Potent cholinesterase inhibitors (e.g., soman, sarin), induce a wide range of deleterious effects including convulsions, behavioral impairments and ultimately, death. Due to the likelihood of various scenarios of military or terrorist attacks by these and other chemical weapons, research has to be aimed at finding optimal therapies. Early accumulation of acetylcholine in synaptic clefts was suggested to trigger an array of toxic events including an excessive release of glutamate, culminating in the activation of its receptors. Stimulation of the N-Methyl-D-Aspartate (NMDA) subtype of these receptors was associated with the neuronal injury that initiates organophosphate-induced brain damage. The notion of a stepwise mechanism yielded treatments based on a combination of an immediate administration of enzyme reactivators and anticholinergic drugs. This strategy dramatically increased survival rates but did not abolish convulsions and failed to prevent the ensuing cognitive dysfunction. Efforts to improve this paradigm by adding anticonvulsants or antiglutamatergic drugs with anti-epileptic characteristics produced dubious results. Under these conditions, benactyzine and caramiphen, agents with anticholinergic and antiglutamatergic properties, provided improved protection when introduced as adjunct agents to oximes, reversible cholinesterase inhibitors and/or specific antimuscarinic drugs such as atropine. In contrast, the specific antimuscarinic drug scopolamine failed to block soman-induced changes in glutamatergic and behavioral parameters even when given prophylactically. These findings along with a large number of additional reports led towards the conclusion that the therapeutic advantage of drugs such as benactyzine and caramiphen could derive from their ability to modulate central cholinergic and glutamate neurotransmission.
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PMID:Therapy against organophosphate poisoning: the importance of anticholinergic drugs with antiglutamatergic properties. 1944 58

Chickens aged 5-6 weeks were inoculated with 3 strains of Newcastle disease virus of differing pathogenicity. The levels of the enzymes lactate dehydrogenase (LDH), isocitrate dehydrogenase (ICDH), cholinesterase (ChE), alkaline and acid phosphatase (ALP and AcP), glutamate-oxaloacetate and glutamate-pyruvate transaminases (GOT and GPT) in serum were measured. Significant decreases in the levels of ChE and ALP were found in chickens infected with high doses of a velogenic strain of virus. The levels of LDH, ICDH and GOT were elevated in these chickens, but the levels of AcP and GPT were unchanged. ALP levels were slightly decreased and LDH levels were slightly elevated in chickens that were inoculated with a mesogenic strain. No significant changes in enzyme levels were found in chickens infected with lentogenic virus. Changes in enzyme levels were found to be correlated with the clinical findings in the infected chicks.
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PMID:Biochemical changes in chicken serum during infection with strains of Newcastle disease virus of differing virulence. I. Enzyme study. 1877 7

We review the main therapeutic targets in Alzheimer's disease. Current treatments include cholinesterase inhibitors and the glutamate-modulating drug memantin. Other neurotransmitters such as serotonin, histamine and noradrenaline may also be targeted. Although useful, however, these symptomatic treatments do not prevent neuronal degeneration and death. Epidemiological studies suggest that treatments given for other reasons, such as antiinflammatory agents (including NSAIDs), cholesterol-lowering drugs, hormone replacement therapy and antioxidants, may prevent or improve Alzheimer-type dementia, but this is not always borne out in controlled clinical trials. Prevention of hypertension significantly reduces the incidence of vascular dementia and of Alzheimer-type dementia, albeit through an unknown mechanism. Alzheimer's disease is characterized by two main lesions: amyloid plaques and neurofibrillary tangles composed of aggregated A Beta peptides and hyperphosphorylated tau. Active and passive immunization against A beta has given promising results. Other exciting approaches include modulation of A beta processing by inhibiting BACE1 or gamma-secretase or upregulating alpha-secretase; A beta peptide catabolism; inhibition of beta fibrillization; and reducing tau phosphorylation or inhibiting tau aggregation. More remote possibilities include gene therapy and the use of growth factors to increase neurogenesis.
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PMID:[Alzheimer's disease: from brain lesions to new drugs]. 1881 89

The percentage of Taiwanese aged 65 years and older has been increasing over the past 27 years, from 4.1% in 1980 to 10.2% in 2007. Studies on the Taiwan population have shown that the prevalence of dementia is approximately 1.7 - 4.3% among aged people, and that the most common cause of dementia is Alzheimer's disease (AD). However, compared to Western countries, this is a low prevalence rate, which might be due to the simple lifestyle led by aged Taiwanese, a selective higher mortality rate in Taiwanese, and a low prevalence of the APOE4 allele in Taiwanese. The current evaluation of dementia in Taiwan derives from several reliable and valid cognitive and behavioral assessment tools originally developed in Western countries. These tools are not only useful for clinical evaluation, but also have offered a method for possible cross-cultural assessment. Behavioral and psychiatric symptoms of dementia in Taiwan have been shown to be similar to other ethnic groups, except for a relative high prevalence of apathy. Although three cholinesterase inhibitors and one glutamate NMDA receptor antagonist are available in Taiwan to treat dementia, their insurance reimbursement is strictly regulated and only a small proportion of patients with AD receive medical treatment. A local consensus of and guideline for diagnosis and treatment of dementia is needed in Taiwan.
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PMID:Dementia in Taiwan: past, present, and future. 1897 20

Although idiopathic Parkinson disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, there are still major unmet needs regarding its long-term management. Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. Current evidence suggests that these are related to mode of administration, whereby multiple oral doses of levodopa generate pulsatile stimulation of striatal dopamine receptors. Current dopamine agonists, while producing more constant plasma levels, fail to match levodopa's efficacy. Strategies to treat levodopa-related motor complications are only partially effective, rarely abolishing motor fluctuations or dyskinesias. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus. Another area of major unmet medical need is related to nondopaminergic and nonmotor symptoms of PD. Targeting transmitter systems beyond the dopamine system is an interesting approach, both for the motor and nonmotor problems of PD. So far, clinical trial evidence regarding 5-HT agonists, glutamate antagonists, adenosine A(2) antagonists and alpha-adrenergic receptor antagonists, has been inconsistent, but trials with cholinesterase inhibitors and atypical antipsychotics to treat dementia and psychosis, have been successful. However, the ultimate goal of PD medical management is modifying disease progression, thereby delaying the evolution of motor and nonmotor complications of advanced disease. As understanding of preclinical markers for PD develops, there is new hope for neuropreventive strategies to target "at risk" populations before clinical onset of disease.
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PMID:Treatments for Parkinson disease--past achievements and current clinical needs. 1922 17

The present study investigated an ethanol extract of the aerial part of Aralia cordata Thunb. (Araliaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid beta (Abeta) protein (25 - 35) in cultured rat cortical neurons and antidementia activity in mice. Exposure of cultured cortical neurons to 10 muM Abeta(25 - 35) for 36 h induced neuronal apoptotic death. At 1 - 10 mug/ml, A. cordata inhibited neuronal death, elevation of intracellular calcium ([Ca(2+)](i)), glutamate release into the medium, and generation of reactive oxygen species (ROS) induced by Abeta(25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 15 nmol Abeta(25-35) was inhibited by chronic treatment with A. cordata (50 and 100 mg/kg, p.o. for 7 days) as measured by a passive avoidance test, and corresponding reductions were observed in brain cholinesterase activity and neuronal death measured histologically in the hippocampal region. Oleanolic acid isolated from A. cordata also inhibited neuronal death, elevation of [Ca(2+)](i), glutamate release, and generation of ROS induced by Abeta(25-35) in cultured rat cortical neurons, suggesting that the neuroprotective effect of A. cordata may be, at least in part, attributable to this compound. From these results, we suggest that the antidementia effect of A. cordata is due to its neuroprotective effect against Abeta(25-35)-induced neurotoxicity and that A. cordata may have a therapeutic role in preventing the progression of Alzheimer's disease.
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PMID:Aralia cordata protects against amyloid beta protein (25-35)-induced neurotoxicity in cultured neurons and has antidementia activities in mice. 1976 45

Galantamine is a cholinesterase inhibitor and allosteric potentiating ligand modulating presynaptic nicotinic acetylcholine receptors that is used in the treatment of Alzheimer disease (AD). The purpose of this study was to determine if galantamine treatment would result in detectable hippocampal metabolite changes that correlated with changes in cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Short echo-time proton magnetic resonance (MR) spectra were acquired from within the right hippocampus of ten patients using a 4 Tesla magnetic resonance imaging (MRI) scanner. Spectra were used to quantify absolute metabolite levels for N-acetylaspartate (NAA), glutamate (Glu), choline (Cho), creatine (Cr), and myo-inositol (mI). Patient scans and cognitive tests were performed before and 4 months after beginning galantamine treatment, which consisted of an 8 mg daily dose for the first month and a 16 mg daily dose for the remaining three months. The levels of Glu, Glu/Cr, and Glu/NAA increased after four months of treatment, while there were no changes in MMSE or ADAS-cog scores. Additionally, changes (Delta) in Glu over the four months (DeltaGlu) correlated with DeltaNAA, and Delta(Glu/Cr) correlated with DeltaMMSE scores. Increased Glu and the ratio of Glu to Cr measured by MR spectroscopy after galantamine treatment were associated with increased cognitive performance. The increase in Glu may be related to the action of galantamine as an allosteric potentiating ligand for presynaptic nicotinic acetylcholine receptors, which increases glutamatergic neurotransmission.
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PMID:Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease. 1983 61

Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, synaptic loss and central cholinergic dysfunction, dysfunction of energy metabolism, and dementia; however, the interactions between these hallmarks remain poorly defined. We studied a well characterized mouse model of amyloid deposition, the doubly transgenic APP(SWE)xPSEN1dE9 mouse. At 10 to 14 months of age, these mice had high levels of amyloid peptides (6.6 microg/g wet weight) and widespread amyloid plaques. Extracellular levels of acetylcholine (ACh) were determined by microdialysis in the hippocampus and were comparable with nontransgenic mice from the same colony. In the open field, both mouse strains responded with a 3-fold increase of hippocampal ACh release. Exploratory behavior of the transgenic mice appeared normal. Infusion of scopolamine evoked 5- to 6-fold increases of ACh levels in both mouse strains. High-affinity choline uptake and cholinesterase activities were identical in both mouse lines. Extracellular levels of glucose and glycerol were similar in control and transgenic mice, whereas lactate levels were slightly (p = 0.06) and glutamate levels significantly (p = 0.02) lower in transgenic mice. Exploration caused increases of glucose and lactate, whereas infusion of scopolamine (1 microM) increased glucose but not lactate. Glutamate levels were increased by scopolamine, whereas glycerol remained constant under all the conditions. We conclude that amyloid peptide production and plaque deposition causes minor changes in cholinergic function and energy metabolites in transgenic mice in vivo. Amyloid peptide formation and/or deposition may not be sufficient for long-term cholinergic or metabolic dysfunction.
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PMID:Neurotransmitters and energy metabolites in amyloid-bearing APP(SWE)xPSEN1dE9 Mouse Brain. 1984 89

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes that requires multitargeted treatment. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) improve cholinergic signaling in the central nervous system and thus AChE inhibitors are well established in the therapy of AD to improve memory disturbances and other cognitive symptoms. On the other hand, AD patients benefit from reduction of pathologic glutamate-induced, Ca(2+)-mediated excitotoxicity by the N-methyl-d-aspartate receptor (NR) antagonist memantine. New drugs that simultaneously affect both cholinergic transmission and glutamate-induced excitotoxicity may further improve AD treatment. While connecting beta-carboline units by alkylene spacers in two different series of compounds and subsequent evaluation of their AChE/BChE-inhibitory potential, we found that several of these bivalent beta-carbolines were potent NR blockers. The most promising compound was a N(9)-homobivalent beta-carboline with a nonylene spacer, which displayed IC(50) values of 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 microM for NR, respectively.
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PMID:Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents. 2036 1

The developmental neurotoxicity of organophosphates involves mechanisms other than their shared property as cholinesterase inhibitors, among which are excitotoxicity and oxidative stress. We used PC12 cells as a neurodevelopmental model to compare the effects of chlorpyrifos and diazinon on the expression of genes encoding glutamate transporters. Chlorpyrifos had a greater effect in cells undergoing nerve growth factor-induced neurodifferentiation as compared to undifferentiated PC12 cells, with peak sensitivity at the initiation of differentiation, reflecting a global upregulation of all the glutamate transporter genes expressed in this cell line. In differentiating cells, chlorpyrifos had a significantly greater effect than did diazinon and concordance analysis indicated no resemblance in their expression patterns. At the same time, the smaller effects of diazinon were highly concordant with those of an organochlorine pesticide (dieldrin) and a metal (divalent nickel). We also performed similar evaluations for the cystine/glutamate exchanger, which provides protection against oxidative stress by moving cystine into the cell; again, chlorpyrifos had the greatest effect, in this case reducing expression in undifferentiated and differentiating cells. Our results point to excitotoxicity and oxidative stress as major contributors to the noncholinesterase mechanisms that distinguish the neurodevelopmental outcomes between different organophosphates while providing a means whereby apparently unrelated neurotoxicants may produce similar outcomes.
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PMID:Transcriptional profiles for glutamate transporters reveal differences between organophosphates but similarities with unrelated neurotoxicants. 2060 Jun 79


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