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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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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 Do not cite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 May 13, 2019 14:25

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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 April 29, 2019 12:33
Increased, Intracellular Calcium overload September 16, 2017 10:15
Neurodegeneration April 04, 2018 14:53
N/A, Cell injury/death December 05, 2018 08:26
Occurrence, Cellular Seizure April 22, 2019 15:17
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
Accumulation, Acetylcholine in synapses leads to Activation, Muscarinic Acetylcholine Receptors February 13, 2019 17:46
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Cellular Seizure April 22, 2019 15:19
Occurrence, Cellular Seizure leads to Increased, glutamate April 22, 2019 15:20
Increased, glutamate leads to Overactivation, NMDARs February 13, 2019 17:47
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload November 29, 2016 20:08
Increased, Intracellular Calcium overload leads to Occurrence, Epileptic seizure February 13, 2019 17:48
Increased, Intracellular Calcium overload leads to N/A, Cell injury/death February 19, 2019 16:25
N/A, Cell injury/death leads to Neurodegeneration February 19, 2019 16:25

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
1 MIE 12 Inhibition, Acetylcholinesterase (AchE) Inhibition, Acetylcholinesterase (AchE)
2 KE 10 Accumulation, Acetylcholine in synapses Accumulation, Acetylcholine in synapses
3 KE 1602 Activation, Muscarinic Acetylcholine Receptors Activation, Muscarinic Acetylcholine Receptors
4 KE 1623 Occurrence, Cellular Seizure Occurrence, Cellular Seizure
5 KE 1350 Increased, glutamate Increased, glutamate
6 KE 388 Overactivation, NMDARs Overactivation, NMDARs
7 KE 389 Increased, Intracellular Calcium overload Increased, Intracellular Calcium overload
8 KE 613 Occurrence, Epileptic seizure Occurrence, Epileptic seizure
9 KE 55 N/A, Cell injury/death N/A, Cell injury/death
10 AO 1514 Neurodegeneration Neurodegeneration

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
Accumulation, Acetylcholine in synapses leads to Activation, Muscarinic Acetylcholine Receptors adjacent High
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Cellular Seizure adjacent
Occurrence, Cellular Seizure leads to Increased, glutamate adjacent
Increased, glutamate leads to Overactivation, NMDARs adjacent High
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload adjacent High
Increased, Intracellular Calcium overload leads to Occurrence, Epileptic seizure adjacent Moderate
Increased, Intracellular Calcium overload leads to N/A, Cell injury/death adjacent High
N/A, Cell injury/death leads to Neurodegeneration adjacent High
Occurrence, Epileptic seizure leads to Increased, glutamate non-adjacent

Network View

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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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Considerations for Potential Applications of the AOP (optional)

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References

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