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Relationship: 2781

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Overactivation, NMDARs leads to Status epilepticus

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Overactivation, NMDARs

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Status epilepticus

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Acetylcholinesterase Inhibition Leading to Neurodegeneration	adjacent	Moderate	Low	Karen Watanabe (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rat	Rattus norvegicus	High	NCBI
guinea pig	Cavia porcellus	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

N-methyl-D-aspartate (NMDA) receptors are ligand and voltage-gated receptors. They require both a post-synaptic depolarization to remove the Mg²⁺ block and binding of glutamate for receptor activation (Kandel et al., 2013). High frequency stimulation that occurs during seizure activity aides in removal of the Mg²⁺ block through depolarization of the affected neuron. The conditions for NMDA receptor activation are ideal as there is prolonged firing and overall increased depolarization during seizure activity (Kapur, 2018). Sustainment of seizure activity for greater than 5 minutes develops into status epilepticus (McDonough and Shih, 1997).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence was collected in multiple ways: literature searches of external databases, review of related KEs and KERS in the AOPWiki, and consultation with experts. Extensive literature searches were conducted in Scopus, Pubmed, and Google Scholar using keywords applicable to each KE, with an initial focus on zebrafish data to then focusing on rat data. Related KEs and KERs in the AOPWiki were also reviewed for relevant evidence and their sources. The “snowball method” was used to find additional articles, i.e., relevant citations within an article were obtained if they provided additional evidence. EndNote reference managing software was used to store results from the literature searches and when possible, a pdf of the manuscript was attached to each record. Papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP. An Excel spreadsheet was used to record reviewed papers and any information worth noting.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

NMDA receptor activation through intraperitoneal administration of NMDA has been shown to cause seizure activity in developing and young adult rats with a marked decrease in effect with age (Mares and Velísek, 1992). NMDA receptors appear to play a role in the upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and downregulation of gamma-aminobutyric acid A (GABA_A) receptors through calcium dependent mechanisms during status epilepticus, which ultimately aids in the self-sustainment of seizure activity (Joshi et al., 2017, Kapur, 2018). Furthermore, seizure termination can be seen to occur with application of NMDA receptor antagonists, as evidenced below.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Status epilepticus induced by exposure to soman in guinea pigs either reduced or arrested after treatment with MK-801, an NMDA receptor antagonist, or was prevented entirely by pretreatment with MK-801 (Sparenborg et al., 1992). An earlier experiment under the same conditions showed similar results (Braitman and Sparenborg, 1989).
Status epilepticus was induced through electrical stimulation in 13–15-week-old male Wistar rats and was successfully terminated using MK-801 (Mazarati and Wasterlain, 1999).
Adult male Sprague-Dawley rats had status epilepticus induced through electrical stimulation which was shown to be refractory to GABAergic drugs, but was still successfully terminated using ketamine, an NMDA receptor antagonist (Borris et al., 2000).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Rats exposed to diisopropylfluorophosphate (DFP) manifested status epilepticus and did not respond to treatment with MK-801 (Deshpande et al., 2010). This is in contrast to the effects seen in the above experiments involving soman or electrical stimulation (Mazarati and Wasterlain, 1999, Sparenborg et al., 1992), suggesting that DFP may include mechanisms that are involved in the initiation and/or maintenance of seizure activity.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The effect of overactivation of NMDA receptors leading to seizure activity has been shown in vertebrate species. Notably, in vivo evidence is provided above in empirical evidence for both rats and guinea pigs (Borris et al., 2000, Braitman and Sparenborg, 1989, Mazarati and Wasterlain, 1999, Sparenborg et al., 1992)

References

List of the literature that was cited for this KER description. More help

Borris, D. J., Bertram, E. H. & Kapur, J. 2000. Ketamine controls prolonged status epilepticus. Epilepsy Res, 42, 117-22. DOI: 10.1016/s0920-1211(00)00175-3.

Braitman, D. J. & Sparenborg, S. 1989. MK-801 protects against seizures induced by the cholinesterase inhibitor soman. Brain Research Bulletin, 23, 145-148. DOI: 10.1016/0361-9230(89)90173-1.

Deshpande, L. S., Carter, D. S., Blair, R. E. & DeLorenzo, R. J. 2010. Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate. Toxicol Sci, 116, 623-31. DOI: 10.1093/toxsci/kfq157.

Joshi, S., Rajasekaran, K., Sun, H., Williamson, J. & Kapur, J. 2017. Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus. Neurobiol Dis, 103, 45-53. DOI: 10.1016/j.nbd.2017.03.017.

Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. 2013. Synaptic Integration in the Central Nervous System. Principles of Neural Science, Fifth Edition. Blacklick, United States: McGraw-Hill Publishing.

Kapur, J. 2018. Role of NMDA receptors in the pathophysiology and treatment of status epilepticus. Epilepsia Open, 3, 165-168. DOI: 10.1002/epi4.12270.

Mares, P. & Velísek, L. 1992. N-methyl-D-aspartate (NMDA)-induced seizures in developing rats. Brain Res Dev Brain Res, 65, 185-9. DOI: 10.1016/0165-3806(92)90178-y.

Mazarati, A. M. & Wasterlain, C. G. 1999. N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat. Neurosci Lett, 265, 187-90. DOI: 10.1016/s0304-3940(99)00238-4.

McDonough, J. H., Jr. & Shih, T. M. 1997. Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev, 21, 559-79. DOI: 10.1016/s0149-7634(96)00050-4.

Sparenborg, S., Brennecke, L. H., Jaax, N. K. & Braitman, D. J. 1992. Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. Neuropharmacology, 31, 357-68. DOI: 10.1016/0028-3908(92)90068-z.