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Relationship: 2783

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

Status epilepticus leads to Increased, Intracellular Calcium overload

Upstream event

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

Status epilepticus

Downstream event

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

Increased, Intracellular Calcium overload

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	High	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 Do not cite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

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

Status epilepticus is defined as continuous seizure activity lasting for more than five minutes, or intermittent seizure activity without regaining of consciousness for the same length of time. Prolonged seizure activity increases neuronal intracellular calcium levels through a variety of mechanisms, such as NMDA receptors, voltage-dependent calcium channels, or release from intracellular calcium stores (Deshpande et al., 2010, Deshpande et al., 2014, Pal et al., 1999).

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

Calcium influx through voltage-gated channels and ionotropic receptors has been shown to occur in in vitro and in vivo experiments through targeted antagonism of those channels (Deshpande et al., 2010, Pal et al., 1999).

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

Male Sprague-Dawley rats exposed to paraoxon (POX) to induce status epilepticus had increased and prolonged intracellular calcium levels in hippocampal neurons. It appeared that this increase was due to intracellular calcium stores given that inhibition of ryanodine / IP3 receptors lowered calcium levels (Deshpande et al., 2014).
Status epilepticus induced in male Sprague-Dawley rats in a pilocarpine model showed increases in intracellular hippocampal calcium levels both immediately after status epilepticus and continued to remain elevated days later. Animals that were exposed to pilocarpine but did not develop seizure activity did not show increased intracellular calcium levels (Raza et al., 2004).
An in vitro model of status epilepticus induced by low magnesium in solution with hippocampal cells obtained from 2-day postnatal Sprague-Dawley rats showed increases in intracellular calcium. This was shown to be influx of calcium as reducing extracellular calcium in solution prevented in rise in intracellular calcium (Pal et al., 1999).
Another in vitro model of status epilepticus, using hippocampal neurons cultured from 2-day postnatal Sprague-Dawley rats, induced by low extracellular magnesium showed sustained increases in intracellular calcium (calcium plateau) following three hours of in vitro status epilepticus. Calcium levels following SE were reduced when treated with Dantrolene, a ryanodine receptor inhibitor, suggesting the plateau could be due to intracellular calcium stores (Nagarkatti et al., 2010).

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

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

Intracellular calcium influx has been demonstrated to occur through multiple in vitro (Nagarkatti et al., 2010, Pal et al., 1999) and ex vivo (Deshpande et al., 2014, Raza et al., 2004) experiments in rat models of status epilepticus.

References

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

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.

Deshpande, L. S., Carter, D. S., Phillips, K. F., Blair, R. E. & DeLorenzo, R. J. 2014. Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication. NeuroToxicology, 44, 17-26. DOI: 10.1016/j.neuro.2014.04.006.

Nagarkatti, N., Deshpande, L. S., Carter, D. S. & DeLorenzo, R. J. 2010. Dantrolene inhibits the calcium plateau and prevents the development of spontaneous recurrent epileptiform discharges following in vitro status epilepticus. Eur J Neurosci, 32, 80-8. DOI: 10.1111/j.1460-9568.2010.07262.x.

Pal, S., Sombati, S., Limbrick, D. D., Jr. & DeLorenzo, R. J. 1999. In vitro status epilepticus causes sustained elevation of intracellular calcium levels in hippocampal neurons. Brain Res, 851, 20-31. DOI: 10.1016/s0006-8993(99)02035-1.

Raza, M., Blair, R. E., Sombati, S., Carter, D. S., Deshpande, L. S. & DeLorenzo, R. J. 2004. Evidence that injury-induced changes in hippocampal neuronal calcium dynamics during epileptogenesis cause acquired epilepsy. Proc Natl Acad Sci U S A, 101, 17522-7. DOI: 10.1073/pnas.0408155101.