Upstream eventIncreased pro-inflammatory mediators
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|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|
Life Stage Applicability
|During brain development, adulthood and aging||High|
Key Event Relationship Description
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 cytolkines/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; Taetsch and Block, 2013). The equimolar production of superoxide and NO from glial cells can lead to high steady levels of peoxynitrite, 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). 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 Supporting this KER
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.
Mercury accumulates in the brain particularly in astrocytes and induce astrocyte swelling, excitatory amino acid release and decreased anti-oxidant protections (Shanker et al., 2003; Allen et al., 2001), features that are also observed in reactive astrocytes. Due to the central role of astrocytes for neuronal function (control of water transport, production of trophic factors, of anti-oxidants, tri-partite synapse,… (Ximeres da Silva, 2016; Bezzi and Volterra, 2001; Hertz and Zielke, 2004; Sidoryk-Wegrzynowicz et al., 2011), it is thought that neuronal dysfunction may be secondary to disturbance in astrocytes (Aschner et al., 2007).
Perinatal exposure (GD7-PD21) of rat to MeHgCl (0.5 mg/kg bw/day) in drinking water lead to gliosis in cerebellum of immature rats (PD21) without affecting the cholinergic system. In contrast, at PD36, astrogliosis was accompanied by an increase of muscarinic M2-immunopositive Bergman cells and a lack of M3 muscarinic receptors in the molecular layer. These results suggest that astrogliosis which is observed first at PD21 may be responsible of the delayed effects of mercury on neurons (Roda et al., 2008).
Developmental exposure of mice from GD8 to PD21 to 50 mM HgCl2 in maternal drinking water: Female offsprings exhibited higher neuroinflammation which is associated with altered social behavior (Zhang et al., 2013).
MG17, a novel triazole derivative, was able to reduce mercury-induced upregulation of IL-1b, IL-6 and TNF-a (measured by RT-PCR) and proved to be protective against mercury-induced neurodegeneration (Matharasala et al., 2017).
Adult rats exposed to MeHg (5mg/kg bw) for 12 consecutive days exhibited piknotic nuclei in cerebellar granule cells, what was reverted by a co-administration of CA074 an inhibitor of cathepsin released by activated microglia. These observations strongly suggest that the mercury–induced neuronal pathological changes are secondary to microglial activation (Sakamoto et al., 2008).
Rats exposed to acrylamide (20 mg/kg bw for 4 weeks) together with farmesol (sequiterpene) showed a downregulation of astrogliosis (i.e. decreased GFAP) and of microgliosis (i.e. decreased Iba1) and of TNF-a, Il-1b and i-NOS in cortex, hippocampus and striatum. This was associated with a marked improvement in motor coordination and a decrease in markers of oxidative stress, as compared to rats exposed to acrylamide alone (Santhanasabapathy et al., 2015).
Uncertainties and Inconsistencies
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).
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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.
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.
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.
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.