
This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Aop: 281
Title
Acetylcholinesterase Inhibition Leading to Neurodegeneration
Short name
Graphical Representation
Point of Contact
Contributors
- Kendra Conrow
- Karen Watanabe
- Natalia Reyero
- Priscilla Pacheco
- Dennis Sinitsyn
- Allie Always
Status
Author status | OECD status | OECD project | SAAOP status |
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Under development: Not open for comment. Do not cite |
This AOP was last modified on July 16, 2022 18:37
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Acetylcholinesterase (AchE) Inhibition | April 29, 2020 17:21 |
Acetylcholine accumulation in synapses | June 26, 2020 13:06 |
Activation, Muscarinic Acetylcholine Receptors | April 17, 2020 13:09 |
Overactivation, NMDARs | June 26, 2020 04:38 |
Increased, Intracellular Calcium overload | June 26, 2020 04:45 |
Cell injury/death | July 15, 2022 09:46 |
Occurrence, Focal Seizure | May 20, 2020 01:40 |
N/A, Neurodegeneration | February 23, 2021 05:07 |
Status epilepticus | May 21, 2020 18:26 |
Increased, glutamate | October 11, 2021 14:58 |
AchE Inhibition leads to ACh Synaptic Accumulation | December 19, 2019 15:57 |
Status epilepticus leads to Overactivation, NMDARs | May 21, 2020 18:20 |
ACh Synaptic Accumulation leads to Activation, Muscarinic Acetylcholine Receptors | February 13, 2019 17:46 |
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure | April 22, 2019 15:19 |
Occurrence, Focal Seizure leads to Overactivation, NMDARs | November 13, 2019 15:33 |
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload | November 29, 2016 20:08 |
Increased, Intracellular Calcium overload leads to Cell injury/death | February 19, 2019 16:25 |
Cell injury/death leads to N/A, Neurodegeneration | November 29, 2016 20:08 |
Increased, Intracellular Calcium overload leads to Status epilepticus | May 21, 2020 18:19 |
Abstract
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 12 | Acetylcholinesterase (AchE) Inhibition | AchE Inhibition |
KE | 10 | Acetylcholine accumulation in synapses | ACh Synaptic Accumulation |
KE | 1602 | Activation, Muscarinic Acetylcholine Receptors | Activation, Muscarinic Acetylcholine Receptors |
KE | 1623 | Occurrence, Focal Seizure | Occurrence, Focal Seizure |
KE | 1350 | Increased, glutamate | Increased, glutamate |
KE | 388 | Overactivation, NMDARs | Overactivation, NMDARs |
KE | 389 | Increased, Intracellular Calcium overload | Increased, Intracellular Calcium overload |
KE | 1788 | Status epilepticus | Status epilepticus |
KE | 55 | Cell injury/death | Cell injury/death |
AO | 352 | N/A, Neurodegeneration | N/A, Neurodegeneration |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
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Status epilepticus leads to Overactivation, NMDARs | non-adjacent |