Upstream eventN/A, Cell injury/death
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||indirectly leads to||Weak|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging||directly leads to||Moderate|
|Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins during brain development leads to impairment of learning and memory||directly leads to|
Life Stage Applicability
How Does This Key Event Relationship Work
The pioneering work of Kreutzberg and coworkers (1995, 1996) has shown that neuronal injury leads to neuroinflammation, with microglia and astrocyte reactivities. Several chemokines and chemokines receptors (fraktalkine, CD200) control the neuron-microglia interactions, and a loss of this control can trigger microglial reactivity (Blank and Prinz, 2013; Chapman et al., 2000; Streit et al., 2001). Upon injury causing neuronal death (mainly necrotic), signals termed Damage-Associated Molecular Patterns (DAMPs) are released by damaged neurons and promote microglial reactivity (Marin-Teva et al., 2011; Katsumoto et al., 2014). Toll-like receptors (TLRs) are pattern-recognition receptors that recognize specific pathogen- and danger-associated molecular signatures (PAMPs and DAMPs) and subsequently initiate inflammatory and immune responses. Microglial cells express TLRs, mainly TLR-2, which can detect neuronal cell death (for review, see Hayward and Lee, 2014). TLR-2 functions as a master sentry receptor to detect neuronal death and tissue damage in many different neurological conditions including nerve trans-section injury, traumatic brain injury and hippocampal excitotoxicity (Hayward and Lee, 2014). Astrocytes, the other cellular mediator of neuroinflammation (Ranshoff and Brown, 2012) are also able to sense tissue injury via TLR-3 (Farina et al., 2007; Rossi, 2015).
Weight of Evidence
It is widely accepted that cell/neuronal injury and death lead to neuroinflammation (microglial and astrocyte reactivities) in adult brain. In the developing brain, neuroinflammation was observed after neurodegeneration induced by excitotoxic lesions (Acarin et al., 1997; Dommergues et al., 2003) or after ethanol exposure (Tiwari et al., 2012; Ahmad et al., 2016). It is important to note that physiological activation of microglial cells is observed during normal brain development for removal of apoptotic debris (Ashwell 1990, 1991). But exposure to toxicant (ethanol), excitotoxic insults (kainic acid) or traumatic brain injury during development can also induce apoptosis in hippocampus and cerebral cortex, as measured either by TUNEL, BID or caspase 3 upregulation associated to an inflammatory response, as evidenced by increased level of pro- inflammatory cytokines IL-1b, TNF-a, of NO, of p65 NF-kB or of the marker of astrogliosis, glial fibrillary acidic protein (GFAP), suggesting that, during brain development, neuroinflammation can also be triggerred by apoptosis induced by several types of insult (Tiwari and Chopra, 2012; Baratz et al., 2015; Mesuret et al., 2014).
Empirical Support for Linkage
Include consideration of temporal concordance here
In 3D cultures prepared from fetal rat brain cells exposed to Pb (10-6 - 10-4 M for 10 days), Pb-induced neuronal death was evidenced by a decrease of cholinergic and GABAergic markers associated to a decrease in protein content, and was accompanied by microglial and astrocyte reactivities (Zurich et al., 2002). These effects were more pronounced in immature than in differentiated cultures (Zurich et al., 2002). In adult rats, exposure to 100 ppm of Pb for 8 weeks caused neuronal death, evidenced by an increase in apoptosis (TUNEL) that was associated with microglial reactivity and an increase in IL-1b, TNF-a and i-NOS expression (Liu et al., 2012). Acute exposure to Pb (25 mg/kg, ip, for 3 days) increased GFAP and glutamate synthetase expression with impaiment of glutamate uptake and probable neuronal injury (Struzunska, 2000; Struzunska et al., 2001).
It is interesting to note that glial cells and in particular astrocytes are able to accumulate lead, suggesting that thes cells may be also a primary target of lead neurotoxic effects (Zurich et al., 1998; Lindhal et al., 1999).
- Astrogliosis is one of the histopathological findings revealed by the assessment of brains derived from patients diagnosed with Amnesic Shellfish Poisoning (ASP) (reviewed in Pulido, 2008). In a reference study, where the brain of a patient after acute DomA intoxication has been examined in great detail gliosis has been detected in the overlying cortex, dorsal and ventral septal nuclei, the secondary olfactory areas and the nucleus accumbens (Cendes et al., 1995). Reactive astrogliosis has also been confirmed in the sixth cortical layer and subjacent white matter in the orbital and lateral basal areas, the first and second temporal gyri, the fusiform gyrus, the parietal parasagittal cortex, and the insula (Cendes et al., 1995).
- Adult rats have been assessed seven days after the administration of DomA (2.25 mg/kg i.p.) and revealed astrocytosis identified by glial fibrillary acidic protein (GFAP)-immunostaining and activation of microglia by GSI-B4 histochemistry (Appel et al., 1997). More investigators have suggested that DomA can activate microglia (Ananth et al., 2001; Chandrasekaran et al., 2004).
- DomA treatment (2 mg/kg once a day for 3 weeks) in mice significantly stimulates the expression of inflammatory mediators, including IL-1β (1.7 fold increase), TNF-α (2 fold increase), GFAP (1.4 fold increase), Cox-2 (3 fold increase), and iNOS (1.6 fold increase) compared to controls (Lu et al, 2013).
- Adult female and male mice have been injected i.p. with 4mg/kg (LD50) of DomA and Real-time PCR has been performed in the brain derived at 30, 60 and 240 min post-injection. The inflammatory response element cyclooxygenase 2 (COX-2) has been found to be 8 fold increased at the 30 and 60 min time points and then showed a descent back toward basal expression levels by 240 min (Ryan et al., 2005).
- Adult male rats treated with 2 mg/kg DomA i.p. have been sacrificed after 3 or 7 d and shown that GFAP and lectin staining could identify regions of reactive gliosis within areas of neurodegeneration but at higher magnifications compared to the ones used for neurodegeneration (Appel et al., 1997; Scallet et al., 2005).
- At 5 days and 3 months following DomA administration of male Wistar rats, a large number of OX-42 positive microglial cells exhibiting intense immunoreactivity in CA1 and CA3 regions of the hippocampus have been detected. With an antibody against GFAP, immunoreactive astrocytes have been found to be sparsely distributed in the hippocampus derived from DomA treated rats after 3 months' time interval (Ananth et al., 2003). At 5 days after the administration of DomA, GFAP positive astrocytes have been found increased in the hippocampus (Ananth et al., 2003).
Uncertainties or Inconsistencies
Sobin and coworkers (2013) described a Pb-induced decrease in dentate gyrus volume associated with microglial reactivity at low dose of Pb (30 ppm), but not at high doses (330 ppm), plausibly due to the death of microglial cells at the high dose of Pb.
Pb decreased IL-6 secretion by isolated astrocytes (Quian et al., 2007). Such a decrease was also observed in isolated astrocytes treated with methylmercury, and was reverted in microglia astrocyte co-cultures, suggesting that cell-cell interactions can modify the response to a toxicant (Eskes et al., 2002). It is interesting to note that glial cells and in particular astrocytes are able to accumulate lead, suggesting that thes cells may be also a primary target of lead neurotoxic effects (Zurich et al., 1998; Lindhal et al., 1999).
Adult male and female Sprague Dawley rats have received a single intraperitoneal (i.p.) injection of DomA (0, 1.0, 1.8 mg/kg) and have been sacrificed 3 h after the treatment. Histopathological analysis of these animals has shown no alterations for GFAP immunostaining in the dorsal hippocampus and olfactory bulb, indicating absence of reactive gliosis (Baron et al., 2013).
The exposed zebrafish from the 36-week treatment with DomA showed no neuroinflammation in brain (Hiolski et al., 2014). At the same time, microarray analysis revealed no significant changes in gfap gene expression, a marker of neuroinflammation and astrocyte activation (Hiolski et al., 2014).
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
Quantitative evalutation of this KER does not exist (gap of knowledge).
Evidence Supporting Taxonomic Applicability
California sea lions that have been exposed to the marine biotoxin DomA developed an acute or chronic toxicosis marked by seizures, whereas histopathological analysis revealed neuroinflammation characterised by gliosis (Kirkley et al., 2014).
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