Key Event Title
Key Event Component
|neuron death in response to oxidative stress||increased|
Key Event Overview
AOPs Including This Key Event
Level of Biological Organization
How This Key Event Works
How this key event works : It is generally accepted that neuronal stress or neuronal mild injury (Nimmerjahn et al., 2005) as well as changes in neuronal activity/excitability (Janigro and Costa, 1987; Xanthos & Sandkühler, 2014) are sufficient to trigger a neuroinflammatory response. These neuronal dysfunctions can manifest as synaptic loss, cytoskeletal instabilities/disturbances, decrease in neurotransmitter levels or in enzymes involved in neurotransmitter synthesis, or others (Monnet-Tschudi et al., 1996 ; Corvino et al., 2013 ; Sanfeliu et al., 2003 ; Stansfield et al 2012 ; Sandström et al., 2014 ; von Tobel et al., 2014). If the neuronal stress is more intense, it can lead to apoptosis or necrosis, also triggering secondarly an neuroinflammatory response (Choi et al., 2010 ; Klintworth et al., 2009).
How It Is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
It is possible to use several markers of neuronal cytoskeleton (e.g. : neurofimanent proteins, NF-L, -M, -H), synapses (e.g.: synaptophysin), neurotransmitters or enzymes involved in neurotransmitter synthesis (e.g.: thyrosine hydroxylase) and look for changes at the mRNA level with quantitative RT-PCR and at the protein level, with immunoblotting (ex. thyrosine hydroxylase, NF-L,-M,-H), immunocytochemistry followed by a quantification, or by enzymatic assays (e.g.: choline acetyltransferase, glutamic acid decarboxylase). Genomic, proteomic and metabolomic approaches are also suitable for a non targeted approach. All these techniques are widely used, but for a recent description in the context of neurotoxicology and neuroinflammation, see Sandström et al., 2014, von Tobel et al., 2014, Monnet-Tschudi et al., 2000).
Evidence Supporting Taxonomic Applicability
Choi WS, Abel G, Klintworth H, Flavell RA, Xia Z (2010) JNK3 mediates paraquat- and rotenone-induced dopaminergic neuron death. J Neuropathol Exp Neurol 69: 511-520
Corvino V, Marchese E, Michetti F, Geloso MC (2013) Neuroprotective strategies in hippocampal neurodegeneration induced by the neurotoxicant trimethyltin. Neurochem Res 38: 240-253
Janigro D, Costa LG (1987) Effects of trimethyltin on granule cells excitability in the in vitro rat dentate gyrus. Neurotoxicol Teratol 9: 33-38
Klintworth H, Garden G, Xia Z (2009) Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release. Neurosci Lett 462: 1-5
Monnet-Tschudi F, Zurich MG, Honegger P (1996) Comparison of the developmental effects of two mercury compounds on glial cells and neurons in aggregate cultures of rat telencephalon. Brain Res 741: 52-59
Monnet-Tschudi F, Zurich MG, Schilter B, Costa LG, Honegger P (2000) Maturation-dependent effects of chlorpyrifos and parathion and their oxygen analogs on acetylcholinesterase and neuronal and glial markers in aggregating brain cell cultures. Toxicol Appl Pharmacol 165: 175-183
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314-1318
Sandström von Tobel, J., D. Zoia, et al. (2014a). "Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures." Toxicol Lett. DOI : 10.1016/j.toxlet.2014.02.001
Sanfeliu C, Sebastia J, Cristofol R, Rodriguez-Farre E (2003) Neurotoxicity of organomercurial compounds. Neurotox Res 5: 283-305
Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR (2012) Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci 127: 277-295
von Tobel, J. S., P. Antinori, et al. (2014b). "Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype." Neurotoxicology 44C: 61-70.
Xanthos DN, Sandkühler J (2014). Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014 Jan;15(1):43-53.