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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)

Demetrio Raldua (b)

Natalia Garcia-Reyero (c)

(a) Arizona State University

(b) IDAEA-CSIC

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

Point of Contact

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Karen Watanabe   (email point of contact)

Contributors

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  • Kendra Conrow
  • Karen Watanabe
  • Natalia Reyero
  • Priscilla Pacheco

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 Do not cite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 21, 2020 18:20

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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
N/A, Cell injury/death March 16, 2020 05:16
Occurrence, Focal Seizure May 20, 2020 01:40
N/A, Neurodegeneration June 13, 2018 08:42
Status epilepticus May 21, 2020 18:26
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 N/A, Cell injury/death February 19, 2019 16:25
N/A, 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

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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 Acetylcholinesterase (AchE) Inhibition AchE Inhibition
2 KE 10 Acetylcholine accumulation in synapses ACh Synaptic Accumulation
3 KE 1602 Activation, Muscarinic Acetylcholine Receptors Activation, Muscarinic Acetylcholine Receptors
4 KE 1623 Occurrence, Focal Seizure Occurrence, Focal Seizure
5 KE 388 Overactivation, NMDARs Overactivation, NMDARs
6 KE 389 Increased, Intracellular Calcium overload Increased, Intracellular Calcium overload
7 KE 1788 Status epilepticus Status epilepticus
8 KE 55 N/A, Cell injury/death N/A, Cell injury/death
9 AO 352 N/A, Neurodegeneration N/A, Neurodegeneration

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
AchE Inhibition leads to ACh Synaptic Accumulation adjacent High Moderate
ACh Synaptic Accumulation leads to Activation, Muscarinic Acetylcholine Receptors adjacent High
Activation, Muscarinic Acetylcholine Receptors leads to Occurrence, Focal Seizure adjacent
Occurrence, Focal Seizure leads to Overactivation, NMDARs adjacent
Overactivation, NMDARs leads to Increased, Intracellular Calcium overload adjacent High
Increased, Intracellular Calcium overload leads to N/A, Cell injury/death adjacent High
N/A, Cell injury/death leads to N/A, Neurodegeneration adjacent High
Increased, Intracellular Calcium overload leads to Status epilepticus adjacent
Status epilepticus leads to Overactivation, NMDARs non-adjacent

Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex 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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