API

Relationship: 1686

Title

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Glutamate dyshomeostasis leads to N/A, Cell injury/death

Upstream event

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Glutamate dyshomeostasis

Downstream event

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N/A, Cell injury/death

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Sex Applicability

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Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
During brain development, adulthood and aging High

Key Event Relationship Description

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Glutamate is the major excitatory neurotransmitter in the mammalian CNS, where it plays key roles in development, learning, memory and response to injury. However, glutamate at high concentrations at the synaptic cleft acts as a toxin, inducing neuronal injury and death (Meldrum, 2000; Ozawa et al., 1998). Glutamate-mediated neurotoxicity has been dubbed as “excitotoxicity”, referring to the consequence of the overactivation of the N-methyl D-aspartate (NMDA)–type glutamate receptors (cf AOP 48), leading to increased Na+ and Ca2+ influx into neurons (Choi, 1992; Pivovarova & Andrews, 2010). Increased intracellular Ca2+ levels are associated with the generation of oxidative stress and neurotoxicity (Lafon-Cazal, 1993). Accordingly, the control of extracellular levels of glutamate dictates its physiological/pathological actions and this equilibrium is maintained primarily by the action of several glutamate transporters (such as GLAST, GLT1, and EAAC1) located on astrocytic cell membranes, which remove the excitatory neurotransmitter from the synaptic cleft, keeping its extracellular concentrations below toxic levels (Anderson and Swanson, 2000; Maragakis and Rothstein, 2001; Szydlowska & Tymianski, 2010).

 

In addition to synaptic transmission, physiological stimulation of glutamate receptors can mediate trophic effects and promote neuronal plasticity. During development, NMDA receptors initiate a cascade of signal transduction events and gene expression changes primarily involving Ca2+-mediated signaling, induced by activation of either Ca2+- permeable receptor channels or voltage-sensitive Ca2+ channels. The consecutive activation of major protein kinase signaling pathways, such as Ras-MAPK/ERK and PI3-K-Akt, contributes to regulation of gene expression through the activation of key transcription factors, such as CREB, SRF, MEF-2, NF-kappaB. Metabotropic glutamate receptors can also engage these signaling pathways, in part by transactivating receptor tyrosine kinases. Indirect effects of glutamate receptor stimulation are due to the release of neurotrophic factors, such as brain derived neurotrophic factor through glutamate-induced release of trophic factors from glia. The trophic effect of glutamate receptor activation is developmental stage-dependent and may play an important role in determining the selective survival of neurons that made proper connections. During this sensitive developmental period, interference with glutamate receptor function may lead to widespread neuronal loss (for review, Balazs, 2006).

Evidence Supporting this KER

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Biological Plausibility

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Glutamate dyshomeostasis and in particular excess of glutamate in the synaptic cleft will lead to overactivation of ionotropic glutamate receptors and cause cell injury/death, as described in AOP 48. The excess of glutamate can result from decreased uptake in astrocytes (Brookes and Kristt, 1989; Aschner et al., 2000), or neurons (Porciuncula et al., 2003; Moretto et al., 2005). But also from the increased release (Reynolds and Raecz, 1987). This neurotoxic cascade involves calcium overload and ROS production leading to oxidative stress (Meldrum, 2000; Ozawa et al., 1998;Lafon-Cazal, 1993; Ceccatelli et al., 2010). Chemicals binding to sulfhydryl (SH)-/seleno-proteins cause a direct oxidative stress by perturbing mitochondrial respiratory chain proteins and by decreasing anti-oxidant defense mechanism (see KER : MIE to KEdown oxidative stress) and an indirect oxidative stress via perturbation of glutamate homeostasis/excitotoxicity. Thus, there may be some redundancy in the empirical support between this KER and the KER linking KEup oxidative stress and KEdown cell injury/death.

Glutamate has been shown to regulate BDNF production (Tao, 1998, 2002). Accordingly, glutamate may also indirectly contribute to cell injury/death by inducing modifications in the brain levels of trophic factors, since it is known that changes in trophic support can lead to cell injury/death, as well as to perturbation in the physiological establishment of neuronal network (for review, Zhao, 2017).

Empirical Evidence

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KEup

Glutamate dyshomeostasis

KEdown

Cell injury/death

species; developmental stage of exposure to stressor

Stressor

Dose or conc.

Duration

Protective/ aggravating evidence

Reference

Dose-dependent increase in glutamate content in cerebral cortex (+ 60% at 12 µmol kg-1)

 

Increased apoptosis rate measured by flow cytometry

(+ 1100% at 12 µmol kg-1)

 

Rat

adult exposure

MeHgCl

4 µmol kg-1

12 µmol kg-1

i.p injection

5 injections per week during 4 weeks

Pretreatment with dextro-methorphan (low-affinity, noncompetitive NMDAR antagonist)

partially decreased Glu content and apoptosis induced by MeHgCl

Feng, 2014

Dose-dependent increase in glutamate content in cerebral cortex (+ 22% at 12 µmol kg-1)

 

Increased apoptosis rate measured by flow cytometry

(+ 850% at 12 µmol kg-1)

 

Rat

adult exposure

MeHgCl

4 µmol kg-1

12 µmol kg-1

i.p injection

5 injections per week during 4 weeks

Pretreatment with memantine (low-affinity, noncompetitive NMDAR antagonist)

partially decreased Glu content and apoptosis induced by MeHgCl

Liu, 2013

Increase in glutamate content in cerebral cortex (1.12 fold at 12 µmol kg-1)

 

Increased apoptosis rate measured by flow cytometry

(+ 630% at 12 µmol kg-1)

 

Rat

adult exposure

MeHgCl

4 µmol kg-1

12 µmol kg-1

i.p injection

5 injections per week during 4 weeks

Pretreatment with MK801 (noncompetitive NMDAR antagonist)

partially decreased apoptosis induced by MeHgCl

Xu, 2012

Decreased glutamine uptake

Reduction in inner mitochondrial membrane potential

Rat

astrocyte cultures

MeHg

1, 5, 10 µM

1 and 5 min

 

Yin, 2007

Changes in intracellular glutamate concentration

Cell death measured by MTT reduction and LDH release

Mouse

astrocytes, neurons in mono- or co-cultures

MeHg

1-50 µM

24h

 

Morken, 2005

Concentration-dependent inhibition of glutamate uptake and stimulation of glutamate release

Cell death measured by MTT reduction

Mouse

cerebellar granule cells in culture

HgCl2

MeHgCl

10-7-10-4 M

10 min

 

Fonfria, 2005

Increased brain extracellular glutamate measured by microdyalisis

 

Rat

adult exposure

MeHg

10, 100 µM

3-5 h

 

 

Juarez, 2002

Decreased glutamate uptake (-46%)

 

Rat

astrocyte cultures

HgCl2

5 µM

5 min

 

Albrecht, 1993

Decreased synaptosomal glutamate released

 

 

Rat

adult exposure

Acrylamide

 

50 mg kg-1

8 days

21 mg kg-1

21 days

p.o.

 

 

LoPachin, 2004

Dose-dependent decreased cortical glutamate concentration

Dose-dependent abnormal neuronal morphology

Rat

Young (3-4 weeks)

Acrylamide

 

5, 15, 30 mg

kg-1

5 injections per week during 4 weeks

gavage

 

Tian, 2015

Concentration-dependent decrease in glutamate uptake

Time- and concentration-dependent decrease in cell viability, measured by cell counting and LDH release

Rat

astrocytes, neurons in mono-cultures

Acrolein

0.25 – 25 µM

3, 6, 12, 24h

 

Lovell, 2000

 

 

Uncertainties and Inconsistencies

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No uncertainty or inconsistency reported yet.

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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Support for the link between glutamate dyshomeostasis and cell injury /death can be found in rats, and mouse. However, as the neurotransmitter glutamate is already found in insects, it is plausible that this KER is valid throughout taxa (Harris, 2014).

References

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Albrecht, J., Talbot, M., Kimelberg, H.K., Aschner, M., 1993. The role of sulfhydryl groups and calcium in the mercuric chloride-induced inhibition of glutamate uptake in rat primary astrocyte cultures. Brain Res 607, 249-254.

Anderson, C.M., Swanson, R.A., 2000. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32, 1-14.

Aschner, M., Yao, C.P., Allen, J.W., Tan, K.H., 2000. Methylmercury alters glutamate transport in astrocytes. Neurochem Int 37, 199-206.

Balazs, R., 2006. Trophic effect of glutamate. Curr Top Med Chem 6, 961-968.

Brookes, N., Kristt, D.A., 1989. Inhibition of amino acid transport and protein synthesis by HgCl2 and methylmercury in astrocytes: selectivity and reversibility. J Neurochem 53, 1228-1237.

Ceccatelli, S., Dare, E., Moors, M., 2010. Methylmercury-induced neurotoxicity and apoptosis. Chem Biol Interact 188, 301-308.

Choi, D.W., 1992. Excitotoxic cell death. J Neurobiol 23, 1261-1276.

Feng, S., Xu, Z., Liu, W., Li, Y., Deng, Y., Xu, B., 2014. Preventive effects of dextromethorphan on methylmercury-induced glutamate dyshomeostasis and oxidative damage in rat cerebral cortex. Biol Trace Elem Res 159, 332-345.

Fonfria, E., Vilaro, M.T., Babot, Z., Rodriguez-Farre, E., Sunol, C., 2005. Mercury compounds disrupt neuronal glutamate transport in cultured mouse cerebellar granule cells. J Neurosci Res 79, 545-553.

Harris, K.D., Weiss, M., Zahavi, A., 2014. Why are neurotransmitters neurotoxic? An evolutionary perspective. F1000Res 3, 179.

Juarez, B.I., Martinez, M.L., Montante, M., Dufour, L., Garcia, E., Jimenez-Capdeville, M.E., 2002. Methylmercury increases glutamate extracellular levels in frontal cortex of awake rats. Neurotoxicol Teratol 24, 767-771.

Lafon-Cazal, M., Pietri, S., Culcasi, M., Bockaert, J., 1993. NMDA-dependent superoxide production and neurotoxicity. Nature 364, 535-537.

Liu, W., Xu, Z., Deng, Y., Xu, B., Wei, Y., Yang, T., 2013. Protective effects of memantine against methylmercury-induced glutamate dyshomeostasis and oxidative stress in rat cerebral cortex. Neurotox Res 24, 320-337.

LoPachin, R.M., Schwarcz, A.I., Gaughan, C.L., Mansukhani, S., Das, S., 2004. In vivo and in vitro effects of acrylamide on synaptosomal neurotransmitter uptake and release. Neurotoxicology 25, 349-363.

Lovell, M.A., Xie, C., Markesbery, W.R., 2000. Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures. Free Radic Biol Med 29, 714-720.

Maragakis, N.J., Rothstein, J.D., 2001. Glutamate transporters in neurologic disease. Arch Neurol 58, 365-370

Meldrum, B.S., 2000. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130, 1007S-1015S.

Moretto, M.B., Funchal, C., Santos, A.Q., Gottfried, C., Boff, B., Zeni, G., Pureur, R.P., Souza, D.O., Wofchuk, S., Rocha, J.B., 2005. Ebselen protects glutamate uptake inhibition caused by methyl mercury but does not by Hg2+. Toxicology 214, 57-66.

Morken, T.S., Sonnewald, U., Aschner, M., Syversen, T., 2005. Effects of methylmercury on primary brain cells in mono- and co-culture. Toxicol Sci 87, 169-175.

Ozawa, S., Kamiya, H., Tsuzuki, K., 1998. Glutamate receptors in the mammalian central nervous system. Prog Neurobiol 54, 581-618.

Pivovarova, N.B., Andrews, S.B., 2010. Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J 277, 3622-3636.

Porciuncula, L.O., Rocha, J.B., Tavares, R.G., Ghisleni, G., Reis, M., Souza, D.O., 2003. Methylmercury inhibits glutamate uptake by synaptic vesicles from rat brain. Neuroreport 14, 577-580.

Reynolds, J.N., Racz, W.J., 1987. Effects of methylmercury on the spontaneous and potassium-evoked release of endogenous amino acids from mouse cerebellar slices. Can J Physiol Pharmacol 65, 791-798.

Szydlowska, K., Tymianski, M., 2010. Calcium, ischemia and excitotoxicity. Cell Calcium 47, 122-129.

Tao, X., West, A.E., Chen, W.G., Corfas, G., Greenberg, M.E., 2002. A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron 33, 383-395.

Tian, S.M., Ma, Y.X., Shi, J., Lou, T.Y., Liu, S.S., Li, G.Y., 2015. Acrylamide neurotoxicity on the cerebrum of weaning rats. Neural Regen Res 10, 938-943.

Xu, B., Xu, Z.F., Deng, Y., Liu, W., Yang, H.B., Wei, Y.G., 2012. Protective effects of MK-801 on methylmercury-induced neuronal injury in rat cerebral cortex: involvement of oxidative stress and glutamate metabolism dysfunction. Toxicology 300, 112-120.

Yin, Z., Milatovic, D., Aschner, J.L., Syversen, T., Rocha, J.B., Souza, D.O., Sidoryk, M., Albrecht, J., Aschner, M., 2007. Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res 1131, 1-10.

Zhao, H., Alam, A., San, C.Y., Eguchi, S., Chen, Q., Lian, Q., Ma, D., 2017. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Brain Res 1665, 1-21.