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Relationship: 1862
Title
Increased, Intracellular Calcium overload leads to Cell injury/death
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite |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
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
Intracellular calcium (Ca2+) increase can occur from influx through various ion channels (Choi, 1988). Overload of intracellular Ca2+ in the cytoplasm leads to endoplasmic reticulum stress, mitochondrial impairment, and overactivated calcium dependent enzymes such as kinases, phosphatases, proteases, lipases, and endonucleases causing cell damage (Faria et al., 2015, Kaur et al., 2014). Ca2+ elevation occurs shortly (before 1 hour) after exposure to certain toxic compounds (Deshpande et al., 2014).
Evidence Collection Strategy
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
Biological Plausibility
It is well known that Ca2+ signaling overload can trigger cell death mechanisms (Zhivotovsky and Orrenius, 2011). Calcium is also known to partially regulate apoptosis under normal conditions through Ca2+ dependent signaling to the mitochondria (Rodrigues et al., 2018).
Empirical Evidence
- Zebrafish models of severe, acute organophosphorus poisoning showed significant calcium signaling pathway changes, characterized by extensive necrosis in the central nervous system. Calcium chelators also reduced the occurrence of this phenotype (Faria et al., 2015).
- Mouse cortical cells showed a decrease in total glutamate-induced cell death when the exposure solution lacked Ca2+ (Choi, 1985).
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Rat hippocampal neurons showed a significant positive correlation between an inability to restore resting intracellular calcium concentrations and cell death (Limbrick et al., 1995).
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Cell death was significantly reduced in a low calcium solution in a low Mg2+ induced in vitro status epilepticus model of rat hippocampal neurons (Deshpande et al., 2008).
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Neocortical neuron cultures of Swiss-Webster mice exposed to various glutamate receptor agonists showed a correlation between increasing intracellular calcium and increasing LDH release into the medium. Antagonizing NMDA receptors additionally showed both a reduction of intracellular calcium accumulation and LDH release in a dose-dependent manner (Hartley et al., 1993).
Uncertainties and Inconsistencies
Total understanding of the complex signaling involved with intracellular Ca2+ has not been fully explored, but there is plenty of evidence supporting the link between Ca2+ and cell death (Nagarkatti et al., 2009). There is also evidence that the pathway of increased Ca2+ makes a difference in the neurotoxicity of the Ca2+ influx, showing NMDAR mediated influx is more lethal compared to other Ca2+ channels (Lau and Tymianski, 2010).
Known modulating factors
Quantitative Understanding of the Linkage
Table 1: Summary of available quantitative data describing responses of cell injury/death to increased intracellular calcium overload. POX = paraoxon. Glu = glutamate.
Upstream Increased Intracellular Ca2+ Overload |
Downstream Cell Injury/Death |
Brief Summary |
Species / Model |
Reference |
|
|
Fura-2 AM Fluorescence |
Fluoro-Jade C (FJC) staining |
Rats received POX injections and were monitored for seizure activity with EEG. Hippocampal neurons were collected at later times and measured for intracellular calcium concentrations. Slices of selected brain regions were stained and measured for cell death. |
Male Sprague-Dawley rats (250-300g | 10-weeks) |
Deshpande et al. (2014) |
||
Fura-2 AM Fluorescence |
Trypan blue (4% final concentration) |
Time-series data of intracellular calcium measured through fluorescence and measurements of percent cell death in cultures exposed to Glu, both alone and with antagonists. |
Cultured rat hippocampal neurons |
Michaels and Rothman (1990) |
||
Fura-2/AM, Fura-2/K+, Fura-2/dextran, BTC |
0.4% Trypan blue exclusion |
Time-series data of intracellular calcium measured through a variety of fluorescence calcium indicators given an application of the selective agonists and measured percent neuronal death. |
Neocortical neurons of Swiss-Webster mice |
Hyrc et al. (1997) |
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Ca2+ cell death is known to occur in both zebrafish and mice (Faria et al., 2015, Choi, 1985).
References
Choi, D. W. 1985. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neuroscience Letters, 58, 293-297. DOI: https://doi.org/10.1016/0304-3940(85)90069-2.
Choi, D. W. 1988. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci, 11, 465-9. DOI: 10.1016/0166-2236(88)90200-7.
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.
Deshpande, L. S., Lou, J. K., Mian, A., Blair, R. E., Sombati, S., Attkisson, E. & DeLorenzo, R. J. 2008. Time course and mechanism of hippocampal neuronal death in an in vitro model of status epilepticus: role of NMDA receptor activation and NMDA dependent calcium entry. Eur J Pharmacol, 583, 73-83. DOI: 10.1016/j.ejphar.2008.01.025.
Faria, M., Garcia-Reyero, N., Padrós, F., Babin, P. J., Sebastián, D., Cachot, J., Prats, E., Arick Ii, M., Rial, E., Knoll-Gellida, A., Mathieu, G., Le Bihanic, F., Escalon, B. L., Zorzano, A., Soares, A. M. & Raldúa, D. 2015. Zebrafish Models for Human Acute Organophosphorus Poisoning. Sci Rep, 5, 15591. DOI: 10.1038/srep15591.
Hartley, D. M., Kurth, M. C., Bjerkness, L., Weiss, J. H. & Choi, D. W. 1993. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci, 13, 1993-2000. DOI: 10.1523/jneurosci.13-05-01993.1993.
Hyrc, K., Handran, S. D., Rothman, S. M. & Goldberg, M. P. 1997. Ionized intracellular calcium concentration predicts excitotoxic neuronal death: observations with low-affinity fluorescent calcium indicators. J Neurosci, 17, 6669-77. DOI: 10.1523/jneurosci.17-17-06669.1997.
Kaur, S., Singh, S., Chahal, K. S. & Prakash, A. 2014. Potential pharmacological strategies for the improved treatment of organophosphate-induced neurotoxicity. Canadian Journal of Physiology and Pharmacology, 92, 893-911. DOI: 10.1139/cjpp-2014-0113.
Lau, A. & Tymianski, M. 2010. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Archiv European Journal of Physiology, 460, 525-542. DOI: 10.1007/s00424-010-0809-1.
Limbrick, D. D., Jr., Churn, S. B., Sombati, S. & DeLorenzo, R. J. 1995. Inability to restore resting intracellular calcium levels as an early indicator of delayed neuronal cell death. Brain Res, 690, 145-56. DOI: 10.1016/0006-8993(95)00552-2.
Michaels, R. L. & Rothman, S. M. 1990. Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci, 10, 283-92. DOI: 10.1523/jneurosci.10-01-00283.1990.
Nagarkatti, N., Deshpande, L. S. & DeLorenzo, R. J. 2009. Development of the calcium plateau following status epilepticus: role of calcium in epileptogenesis. Expert review of neurotherapeutics, 9, 813-824. DOI: 10.1586/ern.09.21.
Rodrigues, M. A., Gomes, D. A. & Nathanson, M. H. 2018. Calcium signaling in cholangiocytes: Methods, mechanisms, and effects. International Journal of Molecular Sciences, 19. DOI: 10.3390/ijms19123913.
Zhivotovsky, B. & Orrenius, S. 2011. Calcium and cell death mechanisms: A perspective from the cell death community. Cell Calcium, 50, 211-221. DOI: 10.1016/j.ceca.2011.03.003.