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)

In the present study plastic neural responses to N-methyl-D-aspartate-induced excitotoxic lesions and the neuroprotective effects of the L-type voltage-dependent Ca(2+) channel antagonist nimodipine were investigated in the rat magnocellular nucleus basalis. Assessment of spontaneous behaviour in the elevated plus maze and small open-field paradigms on day 5 and day 14 post-surgery indicated anxiety and persistent hypoactivity of N-methyl-D-aspartate-lesioned rats, as compared with sham-operated controls. Nimodipine administration significantly alleviated the behavioural deficits. Quantitative histochemical analysis of acetylcholinesterase-positive fibre innervation of the somatosensory cortex and determination of the numbers of choline-acetyltransferase-positive proximal fibre branches of cholinergic projection neurons in the magnocellular nucleus basalis demonstrated a severe cholinergic deficit as a consequence of the excitotoxic lesion 14 days post-surgery. Nimodipine pre-treatment significantly attenuated the loss of cortical cholinergic innervation and preserved the functional integrity of cholinergic projection neurons in the magnocellular nucleus basalis. Double-labelling immunocytochemistry demonstrated increased amyloid precursor protein expression in shrinking and presumably apoptotic choline-acetyltransferase-positive neurons, whereas surviving cholinergic nerve cells were devoid of excessive amyloid precursor protein immunoreactivity. Moreover, as a consequence of N-methyl-D-aspartate infusion, rim-like accumulation of amyloid precursor protein-positive astrocytes was visualized in a penumbra-like zone of the excitotoxic injury. Furthermore, abundant sprouting of serotonergic projection fibres invading the damaged magnocellular nucleus basalis subdivision was demonstrated. Pharmacological blockade by the Ca(2+) antagonist nimodipine significantly attenuated both neuronal and glial amyloid precursor protein immunoreactivity and serotonergic fibre sprouting following N-methyl-D-aspartate infusion. The present data characterize plastic endogenous glial and neuronal responses in the magnocellular nucleus basalis model of acute excitotoxic brain damage. The increased amyloid precursor protein expression may indicate effective means of intrinsic neuroprotection, as secreted amyloid precursor protein isoforms are suggested to play a role in neuronal rescue following excitotoxic injury. From a pharmacological point of view, extensive sprouting of serotonergic projections in the damaged magnocellular nucleus basalis may also counteract N-methyl-D-aspartate excitotoxicity via serotonin-induced inhibition of Ca(2+) currents and membrane hyperpolarization. Hence, lesion-induced changes in spontaneous animal behaviour, such as anxiety and novelty-induced hypoactivity, may well be attributed to the considerable re-distribution of serotonergic projections in the basal forebrain. In conclusion, our present data emphasize a role of neuron-glia and neurotransmitter-system interactions in functional recovery after acute excitotoxic brain injury, and the efficacy of L-type Ca(2+) channel blockade by the selective 1,4-dihydropyridine antagonist nimodipine.
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PMID:Increased amyloid precursor protein expression and serotonergic sprouting following excitotoxic lesion of the rat magnocellular nucleus basalis: neuroprotection by Ca(2+) antagonist nimodipine. 1106 40

The alternative routes of cleavage of the amyloid precursor protein (APP) result in the generation and secretion of both soluble APP and beta-amyloid, the latter being the main component of the amyloid deposits in the brains of individuals with Alzheimer's disease (AD). This study examined the question of whether acetylcholinesterase (AChE) inhibitors can alter the processing of APP and the level of protein kinase C (PKC) in primary rat basal forebrain cultures. Western blotting was used to test two AChE inhibitors (reversible and irreversible) for their ability to enhance the release of APP and PKC content. These inhibitors were ambenonium (AMB) and metrifonate (MTF), at different concentrations. A significant increase was found in the cell-associated APP level in a basal forebrain neuronal culture, and there was an elevation of the APP release into the medium. Increases were similarly observed in the PKC levels after AMB or MTF treatment. The results suggest that these AChE inhibitors promote the non-amyloidogenic route of APP processing, which may be due to their stimulatory effects on PKC. The PKC activation may enhance the alpha-secretase activity and consequently the production of the N-terminal APP. Since both a decreased level of APP secretion and a low activity and level of PKC may be involved in the pathogenesis of AD, it is concluded that the administration of AChE inhibitors to AD patients may facilitate the memory processes and exert a neuroprotective effect.
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PMID:Reversible and irreversible acetylcholinesterase inhibitors cause changes in neuronal amyloid precursor protein processing and protein kinase C level in vitro. 1109 80

The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.
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PMID:Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists. 1112 32

Red blood cell (RBC) acetylcholinesterase (AChE) inhibition has been used as a peripheral surrogate marker for the activity of centrally acting AChE inhibitors (AChEIs) in the treatment of Alzheimer disease. As a valid peripheral surrogate marker, RBC AChE inhibition should reflect the central pharmacodynamic activity of the compound and should demonstrate a relation with cognitive or global improvement in patients with Alzheimer disease. As a useful clinical tool, RBC AChE inhibition should also provide an advantage in dose optimization. However, the application of surrogate markers in research and clinical use is controversial (Prentice, 1989; Gotzsche, 1996; Colburn, 1997; De Gruttola et al., 1997). For instance, surrogate markers that have been identified or applied inappropriately can lead to erroneous conclusions, slowing the drug development process (Colburn, 1997). Also, the validation of surrogate markers for the pharmacodynamic activity of central nervous system drugs is not always possible because samples of brain tissue cannot be analyzed in humans. Finally, although validation of peripheral markers for central nervous system drugs has been approached via analysis of cerebrospinal fluid (Cutler et al., 1998a), few markers have been subjected to such rigorous evaluation in clinical studies. The extent to which measures of peripheral AChE inhibition accurately model central drug activity and therapeutic effectiveness of AChEIs, both as individual agents and as a drug class, is the focus of this review. AChEIs comprise a group of structurally diverse compounds with a wide range of relative specificities for the various molecular species of cholinesterase found in plasma, RBCs, and the brain. Studies of RBC AChE inhibition after administration of AChEIs in animals are of limited utility because of the differential sensitivity of AChEIs for human versus animal forms of AChE, the poor correlation between effective doses in animals and humans, and the lack of standardized measurements of effectiveness. Although clinical studies of donepezil, metrifonate, and eptastigmine have suggested the potential use of RBC AChE inhibition as a predictor of clinical response, the degree of inhibition yielding maximum cognitive improvements was highly variable from compound to compound (30-80%). Further, investigators did not prove a relation between central and peripheral pharmacodynamics or demonstrate an advantage over dose in the ability of RBC AChE inhibition to predict clinical response. A study of rivastigmine in patients with Alzheimer disease revealed that cerebrospinal fluid AChE inhibition correlated well with cognitive performance, whereas peripheral inhibition did not. Therefore, RBC cholinesterase inhibition is not a reliable surrogate marker for the activity of AChEIs as a class of drugs, and its usefulness as a dose optimization tool for individual agents has yet to be demonstrated clearly.
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PMID:RBC cholinesterase inhibition: a useful surrogate marker for cholinesterase inhibitor activity in Alzheimer disease therapy? 1118

Dehydroevodiamine has been reported to have anticholinesterase activity and an anti-amnesic effect. This study examined the effects of dehydroevodiamine on scopolamine- and beta-amyloid peptide-(25--35)-induced amnesia in mice, using a step-through passive avoidance test. Similarly to the cholinesterase inhibitor, physostigmine (0.03--0.3 mg/kg, i.p.), dehydroevodiamine (0.75--12.0 mg/kg, i.p.) administered 30 min before the training trial, immediately after the training trial, and 30 min before the retention test significantly improved scopolamine- and beta-amyloid peptide-(25--35)-induced amnesia. In beta-amyloid peptide-(25--35)-induced amnesia, the rank order of anti-amnesic potency in these three administration schedules for dehydroevodiamine was different from that for physostigmine. Furthermore, dehydroevodiamine was more potent to improve beta-amyloid peptide-(25--35)-induced amnesia than scopolamine-induced amnesia when administered before the training trial. These results suggested that dehydroevodiamine may have an action other than that of an anticholinesterase and may be a novel and effective ligand for improvement of beta-amyloid type amnesia.
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PMID:Dehydroevodiamine attenuates beta-amyloid peptide-induced amnesia in mice. 1122 96

Two features of Alzheimer's disease (AD) are beta-amyloid protein (betaAP) deposition and a severe cholinergic deficit. beta-Amyloid protein is a 39- to 43-amino acid transmembrane fragment of a larger precursor molecule, amyloid precursor protein. It is a major constituent of senile plaque, a neuropathologic hallmark of AD, and has been shown to be neurotoxic in vivo and in vitro. The cholinergic neurotransmission system is seen as the primary target of AD. However, other systems are also found to show functional deficit. An association between cholinergic deficit and betaAP is suggested by a negative correlation between cigarette smoking and AD. Evidence hitherto suggests that betaAP causes neuronal death possibly via apoptosis by disrupting calcium homeostasis, which may involve direct activation or enhancement of ligand-gated or voltage-dependent calcium channels. Selective second messengers such as protein kinases are triggered that signal neuronal death. Nicotine or acetylcholinesterase inhibitors can partially prevent the neurotoxicity of betaAP in vivo and in vitro. However, the exact mechanism by which nicotine provides its protective effects is not fully understood, but clearly there are protective roles for nicotine. Here, some aspects of betaAP neurotoxicity and nicotinic intervention as a protective agent are discussed.
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PMID:Nicotine and its interaction with beta-amyloid protein: a short review. 1123 Aug 73

1. Drugs effective in Alzheimer's disease (AD) should have several aims: to improve the cognitive impairment, control the behavioural and neurological symptoms, delay the progression of the disease, and prevent the onset. In order to attain these targets, cell and animal models are needed on which to test pathogenetic hypothesis and demonstrate the potential effectiveness of new drugs. This overview examines the results obtained in animal models. They are the link between the molecular and biochemical studies on the disease and the reality of human pathology. 2. The development of animal models reproducing the complexity of AD pathogenetic mechanisms and clinical symptoms still represents a challenge for the preclinical investigators. Moreover, the succession of different animal models well documents the progressive widening of our knowledge of the disease with the identification of new therapeutic targets. 3. The main animal models are listed, and their contribution to the understanding of the pathogenic mechanisms and development of the drugs presently used in AD therapy is described. Moreover, their role in the study of future drugs is analysed 4. Preclinical studies on cholinesterases and animal models mimicking the cholinergic hypofunction occurring in AD have been instrumental in developing cholinesterase inhibitors, which are the only recognised drugs for the symptomatic treatment of AD. 5. Artificially created beta-amyloid (A beta) deposits in normal rats, and transgenic mice overexpressing amyloid precursor protein (APP) are the models on which the future treatment are tested. They are aimed to prevent formation of A beta deposits or its transformation in neuritic plaques. 6. Models of brain inflammation, aging animals, and models of brain glucose and energy metabolism impairment make it possible to identify and assess the activity of anti-inflammatory agents, antioxidants, ampakines and other potentially active agents. 7. It is concluded that the present level of information on AD could never have been reached without preclinical studies, and the development of new drugs will always require extensive preclinical investigations.
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PMID:Overview and perspective on the therapy of Alzheimer's disease from a preclinical viewpoint. 1126 52

The extracellular deposition of amyloid beta-peptide (Abeta) in the form of cerebrovascular amyloid and extracellular plaques is one of the major neuropathological manifestations of Alzheimer's disease (AD). Abeta is generated proteolytically from the large beta-amyloid precursor protein (APP). APP is cleaved by a group of proteases called "secretase" to generate soluble derivatives of APP (sAPP), which are secreted in human plasma, CSF and cultured cells. Neurochemically, there is a severe loss of cholinergic neurons and a decreased synthesis of acetylcholine in neocortex in AD. Current approved AD drugs, such as aricept and tacrine, are based on the use of cholinesterase inhibitors (ChEIs) and have been reported to improve memory deficits and cognitive decline in some patients with AD. To compare the effects of ChEIs on APP processing, we have tested a series of ChEIs such as tacrine, physostigmine, metrifonate, phenserine and cymserine in cultured human neuroblastoma cells. We analyzed levels of sAPP by immunochemical techniques with APP-specific antibodies and assayed levels of Abeta by a sensitive sandwich ELISA. Based on these results, ChEIs can be divided into three groups: the first group of ChEIs had no effect on sAPP secretion, the second decreased the sAPP secretion only, and third group affected the secretion of sAPP and Abeta. The difference in the action of metrifonate, physostigmine, phenserine and tacrine on APP processing is independent of their selectivity for the cholinesterase enzymes. This possibly is due to the different targets that are used by ChEIs. Studying the effects of ChEIs on different targets is useful to maximize the benefit of ChEIs for the treatment of AD subjects.
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PMID:Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer's disease. 1127 93

A growing consensus indicates that Alzheimer's disease (AD) results from an increase in the production or accumulation of beta-amyloid protein (A beta) leading to nerve cell death. Mechanisms by which A beta accumulation leads to neuronal death include oxidative damage and inflammation. This article discusses the management of AD patients with antioxidants, cholinesterase inhibitors, and psychotropic agents. Studies show that these agents can slow the progression of the disease, improve cognition, and reduce behavioral disturbances. A therapeutic alliance between physician and caregiver is an essential element in successfully managing the AD patient. The 3Rs--repeat, reassure, and redirect--can help caregivers reduce behavioral disturbances in patients with AD and limit the need for pharmacologic management.
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PMID:Treatment of Alzheimer's disease. 1143 20

During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer's disease (AD) resulted in three drugs being registered for the first time in the US and Europe. All three compounds are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a stable level during a 6-month to 1-year period of treatment, as compared to placebo. Additional drug effects are to slow down cognitive deterioration and improve behavioral and daily living activity. Recent studies show that in many patients the cognitive stabilization effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic, and directly cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and amyloid precursor protein (APP) metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and cholinergic synaptic function; the effect of such lesions can be reversed by ChEI treatment. A reduction in cholinergic neurotransmission, experimental or pathological, leads to amyloidogenic metabolism and contributes to the development of neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, for which evidence is available on an experimental as well as clinical level, a mechanism based on beta-amyloid metabolism is postulated. The question whether cholinergic stabilization implies simply slowing down progression of disability or also involves delay of disease progression is discussed.
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PMID:Is anti-cholinesterase therapy of Alzheimer's disease delaying progression? 1144 6


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