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Aop: 281

AOP Title

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Acetylcholinesterase Inhibition Leading to Neurodegeneration

Short name:

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AChE Inhibition Leading to Neurodegeneration

Graphical Representation

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Click to download graphical representation template

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Authors

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Kendra Conrow (a)

Karen H. Watanabe (a)

Natalia Garcia-Reyero (b)

(a) Arizona State University,

(b) US Army Corps of Engineers, Engineering Research and Development Center

Point of Contact

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Kendra Conrow   (email point of contact)

Contributors

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  • Kendra Conrow
  • Karen Watanabe
  • Natalia Reyero

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on February 13, 2019 17:49

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Revision dates for related pages

Page Revision Date/Time
Inhibition, Acetylcholinesterase (AchE) September 16, 2017 10:14
Accumulation, Acetylcholine in synapses September 16, 2017 10:14
Activation, Muscarinic Acetylcholine Receptors February 06, 2019 20:02
Increased, glutamate June 02, 2017 11:32
Overactivation, NMDARs September 16, 2017 10:15
Occurrence, Epileptic seizure June 06, 2018 12:55
Increased, Intracellular Calcium overload September 16, 2017 10:15
Inhibition, Acetylcholinesterase (AchE) leads to Accumulation, Acetylcholine in synapses November 29, 2016 19:53
Occurrence, Epileptic seizure leads to Increased, glutamate February 13, 2019 17:49
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload November 29, 2016 20:08
Accumulation, Acetylcholine in synapses leads to Activation, Muscarinic Acetylcholine Receptors February 13, 2019 17:46
Activation, Muscarinic Acetylcholine Receptors leads to Increased, glutamate February 13, 2019 17:47
Increased, glutamate leads to Overactivation, NMDARs February 13, 2019 17:47
Increased, Intracellular Calcium overload leads to Occurrence, Epileptic seizure February 13, 2019 17:48

Abstract

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The enzyme acetylcholinesterase (AChE) hydrolyzes acetylcholine (ACh) in order to eliminate it from the body.  When AChE is inhibited ACh levels increase. An excess of ACh at cholinergic synapses overstimulates both muscarinic- and nicotinic- receptors (1,2). These receptors are found in most organs in the body, thus the effects of AChE inhibition can result in multiple adverse outcomes affecting a wide variety of functions (1). This AOP focuses upon an acute outcome of neurodegeneration due to AChE inhibition specifically through calcium dysregulation as that has been identified as central to the development of the most severe phenotype caused by acute organophosphate poisoning (3).

1. United States., Environmental Protection Agency., Office of Pesticide Programs. (2000). The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and Carbamate Pesticides. https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf accessed Nov. 2018.

2. Quick, M. W., & Lester, R. A. J. (2002). Journal of Neurobiology, 53(4), 457-478. doi:10.1002/neu.10109.

3. Faria et al. (2015). Scientific Reports, 5. doi:10.1038/srep15591.


Background (optional)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
MIE 12 Inhibition, Acetylcholinesterase (AchE) Inhibition, Acetylcholinesterase (AchE)
KE 10 Accumulation, Acetylcholine in synapses Accumulation, Acetylcholine in synapses
KE 1602 Activation, Muscarinic Acetylcholine Receptors Activation, Muscarinic Acetylcholine Receptors
KE 1350 Increased, glutamate Increased, glutamate
KE 388 Overactivation, NMDARs Overactivation, NMDARs
KE 389 Increased, Intracellular Calcium overload Increased, Intracellular Calcium overload
KE 613 Occurrence, Epileptic seizure Occurrence, Epileptic seizure

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
Inhibition, Acetylcholinesterase (AchE) leads to Accumulation, Acetylcholine in synapses adjacent High Moderate
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload adjacent High
Accumulation, Acetylcholine in synapses leads to Activation, Muscarinic Acetylcholine Receptors adjacent High
Activation, Muscarinic Acetylcholine Receptors leads to Increased, glutamate adjacent Moderate
Increased, glutamate leads to Overactivation, NMDARs adjacent High
Increased, Intracellular Calcium overload leads to Occurrence, Epileptic seizure adjacent Moderate
Occurrence, Epileptic seizure leads to Increased, glutamate non-adjacent

Network View

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Life Stage Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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