Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the normal dog we have found that cholinesterase and tyrosine hydroxylase (TH) histochemistry define a mosaic structure of the caudate nucleus that is similar to that described in other species. To determine if nigrostriatal afferents interlocked with this mosaic we injected dogs with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin specific to dopaminergic nigrostriatal cells. Alternate sections in the caudate nucleus stained for acetylcholinesterase, TH, and terminal degeneration revealed that the areas of densest degeneration were localized to the matrix, thereby outlining areas of much lighter degeneration which were coincident with the patches. This pattern of terminal degeneration suggests the existence of subcomponents of the dopaminergic nigrostriatal pathway, at least one of which might be selectively vulnerable to MPTP.
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PMID:MPTP produces a pattern of nigrostriatal degeneration which coincides with the mosaic organization of the caudate nucleus. 290 3

Administration of the irreversible cholinesterase inhibitor isoflurophate (diisopropylfluorophosphate, DFP) before 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enhanced the loss in tyrosine hydroxylase activity and dopamine and 3,4-dihydroxy-phenylacetic acid content in the striatum of mice in a dose-dependent manner. The effect of DFP on the MPTP-induced changes of dopaminergic markers was evident 30 days after initiating treatment, suggesting augmented neurotoxicity. Neurotoxicity was also enhanced by prior treatment with nicotine, carbachol or oxotremorine. We conclude that activation of either muscarinic or nicotinic receptors enhances the neurotoxicity of MPTP.
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PMID:Enhanced MPTP neurotoxicity after treatment with isoflurophate or cholinergic agonists. 791 17

Balanced dopaminergic cholinergic interactions are crucial for proper basal ganglia function. This is dramatically demonstrated by the worsening of Parkinson's disease symptoms following acetylcholinesterase (AChE) inhibition. Typically, in the brain, the synapse-anchored synaptic AChE (AChE-S) variant is prevalent whereas the soluble readthrough AChE (AChE-R) variant is induced in response to cholinesterase inhibition or stress. Because of the known functional differences between these variants and the fact that AChE-R expression is triggered by various stimuli that themselves are often associated with Parkinson's disease risk, we hypothesized that the splice shift to AChE-R plays a functional role in Parkinsonian progression. After establishing that Paraoxon-induced AChE inhibition indeed aggravates experimental Parkinsonism triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, we tested the roles of individual AChE variants by exposing transgenic mice overexpressing either the AChE-S or AChE-R variant to MPTP. Differential reductions of tyrosine hydroxylase levels in the striatum and substantia nigra indicated that transgenic AChE-R expression confers resistance as compared with the parent FVB/N strain. In contrast, AChE-S overexpression accelerated the MPTP-induced damage. Survival, behavioral measures and plasma corticosterone levels were also compatible with the extent of the dopaminergic damage. Our findings highlight the functional differences between individual AChE variants and indicate that a naturally occurring stress or AChE inhibitor-induced splicing shift can act to minimize dopaminergic cholinergic imbalances. We propose that inherited or acquired alternative splicing deficits could accelerate Parkinsonism and that, correspondingly, adaptive alternative splicing events may attenuate disease progression.
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PMID:Adaptive acetylcholinesterase splicing patterns attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice. 1681 80

Many cell culture models are available for the in vitro assessment of neurotoxicity. The use of three culture types has been investigated: neuroblastoma cell lines, primary cultures of rat and chick midbrain, and organotypic whole brain reaggregate cultures. A tiered system has been proposed involving hierarchical testing through three layers of different neural complexities. This scheme is currently undergoing validation under the auspices of FRAME/EC using 40 test chemicals. To determine the performance and suitability of these culture models studies on selected neurotoxins have been performed: ethylcholine mustard aziridinium, vincristine, aluminium, glutamate, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and T(3)-deprivation. Aspects of this work are described, including mechanistic investigations in rat brain reaggregate cultures. In vitro exposure of xenobiotics through a tiered testing system (ranging from simple cell-based assays measuring cytotoxicological parameters to more complex markers in organotypic cultures) may permit detection of central nervous system neurotoxicity in the contexts of both 'screening' and mechanistics. The degree of simplicity, automaticity and transportability of the tests requires consideration as will the possibility of endpoints for specific classes of chemicals, for example cholinesterase for organophosphorus insecticides. Factors such as extrapolation from the central nervous system to the peripheral nervous system, metabolic activation, the blood-brain barrier, degree of neural cell activation, repair mechanisms, and developing versus adult nervous systems are considered.
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PMID:New models for the In vitro assessment of neurotoxicity in the nervous system and the preliminary validation stages of a 'tiered-test' model. 2073 53

Parkinson's disease (PD) is a complex neurodegenerative disorder with multifactorial pathologies, including progressive loss of dopaminergic (DA) neurons, oxidative stress, mitochondrial dysfunction, and increased monoamine oxidase (MAO) enzyme activity. There are currently only a few agents approved to ameliorate the symptoms of PD; however, no agent is able to reverse the progression of the disease. Due to the multifactorial pathologies, it is necessary to develop multifunctional agents that can affect more than one target involved in the disease pathology. We have designed and synthesized a series of new multifunctional anti-Parkinson's compounds which can protect cerebral granular neurons from 1-methyl-4-phenylpyridinium (MPP+) insult, scavenge free radicals, and inhibit monoamine oxidase (MAO)/cholinesterase (ChE) activities. Among them, MT-20R exhibited the most potent MAO-B inhibition both in vitro and in vivo. We further investigated the neuroprotective effects of MT-20R using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. In vivo, MT-20R alleviated MPTP-induced motor deficits, raised the striatal contents of dopamine and its metabolites, and restored the expression of tyrosine hydroxylase (TH) and the number of TH-positive DA neurons in the substantia nigra. Additionally, MT-20R enhanced the expression of Bcl-2, decreased the expression of Bax and Caspase 3, and activated the AKT/Nrf2/HO-1 signaling pathway. These findings suggest that MT-20R may be a novel therapeutic candidate for treatment of PD.
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PMID:Neuroprotective Effects and Mechanisms of Action of Multifunctional Agents Targeting Free Radicals, Monoamine Oxidase B and Cholinesterase in Parkinson's Disease Model. 2814 26