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Relationship: 1687

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

Neuroinflammation leads to Cell injury/death

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory adjacent Moderate Marie-Gabrielle Zurich (send email) Under development: Not open for comment. Do not cite EAGMST Approved

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
mouse Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male
Female

Life Stage Applicability

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

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

Cells of the innate (microglia and astrocytes) and of the adaptive (infiltrating monocytes and lymphocytes) immune system of the brain have various ways to kill neighboring cells. This is in part due to evolutionary-conserved mechanisms evolved to kill virus-infected cells or tumor cells; in part it is a bystander phenomenon due to the release of mediators that should activate other cells and contribute to the killing of invading micro-organisms. An exaggerated or unbalanced activation of immune cells can thus lead to parenchymal (neuronal) cell death (Gehrmann et al., 1995). Mediators known to have such effects comprise components of the complement system and cytokines/death receptor ligands triggering programmed cell death (Dong and Benveniste, 2001). Various secreted proteases (e.g. matrix metalloproteases), lipid mediators (e.g. ceramide or gangliosides) or reactive oxygen species can contribute to bystander death of neurons (Chao et al., 1995; Nakajima et al., 2002; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013). The equimolar production of superoxide and NO from glial cells can lead to high steady levels of peroxynitrite, which is a very potent cytotoxicant (Yuste et al., 2015). Already stressed neurons, with an impaired anti-oxidant defence system, are more sensitive to such mediators (Xu et al., 2015). Healthy cells continuously display anti "eat-me" signals, while damaged and stressed neurons/neurites display "eat-me" signals that may be recognized by microglia as signals to start phagocytosis (Neher et al., 2012) or by astrocytes (Wakida et al., 2018; Byun and Chung, 2018; Gomez-Arboledas et al., 2018; Morizawa et al., 2017). Reactive astrocytes are also able to release neurotoxic molecules (Mena and Garcia de Ybenes, 2008; Niranjan, 2014). However, astrocytes may also be protective due to their capacity to quench free radicals and secrete neurotrophic factors. The activation of astrocytes may reduce neurotrophic support to neurons (for review, Mena and Garcia de Ybenes, 2008).

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 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

In vitro co-culture experiments have demonstrated that reactive glial cells (microglia and astrocytes) can kill neurons (Chao et al., 1995; Brown and Bal-Price, 2003; Kraft and Harry, 2011; Taetzsch and Block, 2013) and that interventions with e.g. i-NOS inhibition can rescue the neurons (Yadav et al., 2012; Brzozowski et al., 2015). Drugs that block Toll like receptor pathways, which are expressed by glial cells have been proven to be protective by decreasing ROS and RNS production (Lucas et al., 2013).

Reactive microglia can remove synapses, a process known as synapse stripping (Banati et al., 1993; Kettenmann et al., 2013). Reactive astrocytes were also associated with neurite and synapse reduction (Calvo-Ochoa et al., 2014). Microglia can modulate synapse plasticity, an effect mediated by cytokines. During development, microglia can promote synaptogenesis or engulf synapses, a process known as synaptic pruning (for review, Jebelli et al., 2015). It is hypothesized that alterations in microglia functioning during synapse formation and maturation of the brain can have significant long-term effects on the final established neural circuits (for review, Harry and Kraft, 2012). The fact that astrocytes can receive and respond to the synaptic information produced by neuronal activity, owing to their expression of a wide range of neurotransmitter receptors, has given rise to the concept of tripartite synapse (for review, Perez-Alvarez and Araque, 2013; Bezzi and Volterra, 2001). Pro-inflammatory cytokines, such as TNF-a, IL-1b and IL-6, which are produced by reactive astrocytes, are on one side implicated in synapse formation and scaling, long-term potentiation and neurogenesis (for review, Bilbo and Schwartz, 2009) and on the other side can kill neurons (Chao et al., 1995; Kraft and Harry, 2011). Taken together, this suggests that neuron-glia interactions are tightly regulated and that an imbalance, such as increased or long-term release of these inflammatory mediators may lead to deleterious effects on neurons.

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

In 3D rat brain cell-cultures, co-administration of the pro-inflammatory cytokine IL-6 (10 ng/ml) together with non-cytotoxic concentrations of MeHgCl (3 x 10-7 M) for 10 days protected from the mercury-induced decreased in MAP2 immunostaining, suggesting a positive effect of IL-6, in accord with its descibed trophic activity (Eskes et al., 2002).

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
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

Most experimental evidences derived from mouse and rat studies.

References

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

Allen, J.W., Shanker, G., Aschner, M., 2001. Methylmercury inhibits the in vitro uptake of the glutathione precursor, cystine, in astrocytes, but not in neurons. Brain Res. 894, 131-40.

Aschner, M., et al., 2007. Involvement of glutamate and reactive oxygen species in methylmercury neurotoxicity. Braz J Med Biol Res. 40, 285-91.

Banati, R.B., et al., 1993. Cytotoxicity of microglia. Glia. 7, 111-8.

Bezzi, P., Volterra, A., 2001. A neuron-glia signalling network in the active brain. Curr Opin Neurobiol. 11, 387-94.

Bilbo, S.D., Schwarz, J.M., 2009. Early-life programming of later-life brain and behavior: a critical role for the immune system. Front Behav Neurosci. 3, 14.

Brown GC, Bal-Price A. 2003. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27(3): 325-355.

Brzozowski MJ, Jenner P, Rose S. 2015. Inhibition of i-NOS but not n-NOS protects rat primary cell cultures against MPP(+)-induced neuronal toxicity. J Neural Transm 122(6): 779-788.

Byun YG, Chung WS., A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes., J Vis Exp. 2018 Feb 5;(132). doi: 10.3791/56647.

Calvo-Ochoa, E., et al., 2014. Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus. J Cereb Blood Flow Metab. 34, 1001-8.

Chao CC, Hu S, Peterson PK. 1995. Glia, cytokines, and neurotoxicity. CritRevNeurobiol 9: 189-205.

Dong Y, Benveniste EN. 2001. Immune Function of Astrocytes. Glia 36: 180-190.

Eskes C, Honegger P, Juillerat-Jeanneret L, Monnet-Tschudi F. 2002. Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotection via interactions with astrocytes and IL-6 release. Glia 37(1): 43-52.

Gehrmann J, Banati RB, Wiessnert C, Hossmann KA, Kreutzberg GW. 1995. Reactive microglia in cerebral ischaemia: An early mediator of tissue damage? NeuropatholApplNeurobiol 21: 277-289.

Gomez-Arboledas A, Davila JC, Sanchez-Mejias E, Navarro V, Nuñez-Diaz C, Sanchez-Varo R, Sanchez-Mico MV, Trujillo-Estrada L, Fernandez-Valenzuela JJ, Vizuete M, Comella JX, Galea E, Vitorica J, Gutierrez A., Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease., Glia. 2018 Mar;66(3):637-653. doi: 10.1002/glia.23270. Epub 2017 Nov 27.

Harry, G.J., Kraft, A.D., 2012. Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology. 33, 191-206.

Hertz, L., Zielke, H.R., 2004. Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci. 27, 735-43.

Jebelli, J., et al., 2015. Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity? Ann N Y Acad Sci. 1351, 1-10.

Kettenmann, H., Kirchhoff, F., Verkhratsky, A., 2013. Microglia: new roles for the synaptic stripper. Neuron. 77, 10-8.

Kraft AD, Harry GJ. 2011. Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. International journal of environmental research and public health 8(7): 2980-3018.

Lucas, K., Maes, M., 2013. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 48, 190-204.

Matharasala, G., Samala, G., Perumal, Y., 2017. MG17, a novel triazole derivative abrogated neuroinflammation and related neurodegenerative symptoms in rodents. Curr Mol Pharmacol.

Mena MA, Garcia de Yebenes J. 2008. Glial cells as players in parkinsonism: the "good," the "bad," and the "mysterious" glia. Neuroscientist 14(6): 544-560.

Morizawa YM, Hirayama Y, Ohno N, Shibata S, Shigetomi E, Sui Y, Nabekura J, Sato K, Okajima F, Takebayashi H, Okano H, Koizumi S., Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway., Nat Commun. 2017 Jun 22;8(1):28. doi: 10.1038/s41467-017-00037-1. Erratum in: Nat Commun. 2017 Nov 14;8(1):1598.

Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. 2002. Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro. J Neurochem 80: 697-705.

Niranjan R. 2014. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson's disease: focus on astrocytes. Mol Neurobiol 49(1): 28-38.

Neher JJ, Neniskyte U, Brown GC. 2012. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Frontiers in pharmacology 3: 27.

Perez-Alvarez, A., Araque, A., 2013. Astrocyte-neuron interaction at tripartite synapses. Curr Drug Targets. 14, 1220-4.

Roda, E., et al., 2008. Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat. J Chem Neuroanat. 35, 285-94.

Sakamoto, M., et al., 2008. Possible involvement of cathepsin B released by microglia in methylmercury-induced cerebellar pathological changes in the adult rat. Neurosci Lett. 442, 292-6.

Shanker, G., Syversen, T., Aschner, M., 2003. Astrocyte-mediated methylmercury neurotoxicity. Biol Trace Elem Res. 95, 1-10.

Santhanasabapathy, R., et al., 2015. Farnesol quells oxidative stress, reactive gliosis and inflammation during acrylamide-induced neurotoxicity: Behavioral and biochemical evidence. Neuroscience. 308, 212-27.

Sidoryk-Wegrzynowicz, M., et al., 2011. Role of astrocytes in brain function and disease. Toxicol Pathol. 39, 115-23.

Taetzsch T, Block ML. 2013. Pesticides, microglial NOX2, and Parkinson's disease. J Biochem Mol Toxicol 27(2): 137-149.

Wakida NM, Cruz GMS, Ro CC, Moncada EG, Khatibzadeh N, Flanagan LA, Berns MW., Phagocytic response of astrocytes to damaged neighboring cells., PLoS One. 2018 Apr 30;13(4):e0196153. doi: 10.1371/journal.pone.0196153. eCollection 2018.

Ximenes-da-Silva, A., 2016. Metal Ion Toxins and Brain Aquaporin-4 Expression: An Overview. Front Neurosci. 10, 233.

Xu, S., et al., 2015. Wogonin prevents rat dorsal root ganglion neurons death via inhibiting tunicamycin-induced ER stress in vitro. Cell Mol Neurobiol. 35, 389-398.

Yadav, S., et al., 2012. Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson's disease phenotype in the mouse. Neurochem Res. 37, 875-84.

Yuste, J.E., et al., 2015. Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci. 9, 322.

Zhang, Y., Bolivar, V.J., Lawrence, D.A., 2013. Maternal exposure to mercury chloride during pregnancy and lactation affects the immunity and social behavior of offspring. Toxicol Sci. 133, 101-11.