Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress

Murphy, Timothy H.; Miyamoto, Masaomi; Sastre, Antonio; Schnaar, Ronald L.; Coyle, Joseph T.

doi:10.1016/0896-6273(89)90043-3

Cited by 939 publications

(754 citation statements)

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“…The initial evidence for an apoptotic mechanism was that internucleosomal DNA fragmentation was triggered by glutamate in cultured cortical neurons (Kure et al, 1991). However, later studies showed that this could be attributable to decreased glutathione instead of the conventional receptor-mediated toxicity (Murphy et al, 1989;Ratan et al, 1994). Other reports argue against an apoptotic mechanism (Dessi et al, 1993;Csernansky et al, 1994).…”

Section: Discussionmentioning

confidence: 94%

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

1997

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Impaired energy metabolism may play an important role in neuronal cell death after brain ischemia and in late-onset neurodegenerative diseases. Both excitotoxic necrosis and apoptosis have been implicated in cell death induced by metabolic impairment. However, the factors that determine whether cells undergo apoptosis or necrosis are not known. In the present study, metabolic impairment was induced by 3-nitropropionic acid (3-NP), a suicide inhibitor of succinate dehydrogenase. Treatment of cultured rat hippocampal neurons with 3-NP resulted in two types of cell death with distinct morphological, pharmacological, and biochemical features. A rapid necrotic cell death, characterized by cell swelling and nuclear shrinkage, could be completely prevented by the NMDA receptor antagonist MK-801 (10 M) and dose-dependently potentiated by low micromolar levels of extracellular glutamate. A slowly evolving apoptotic death, characterized by nuclear fragmentation, was not attenuated by MK-801 but was prevented by cycloheximide (1 g/ml). The combination of MK-801 and cycloheximide resulted in an almost complete protection against 3-NP-induced cell death. DNA fragmentation, detected by the terminal deoxynucleotidyl transferase-mediated dUTP-X 3Ј nick end-labeling technique, was a late event in apoptosis and also occurred after necrotic cell death. ATP depletion was an early event in the 3-NP-induced neuronal degeneration, and the decline in ATP was exacerbated by glutamate. We conclude that 3-NP triggers two separate cell death pathways: an excitotoxic necrosis as a result of NMDA receptor activation and a delayed apoptosis that is NMDA receptor-independent. Mildly elevated levels of extracellular glutamate shift the cell death mechanism from apoptosis to necrosis.Key words: energy metabolism; succinate dehydrogenase; 3-nitropropionic acid; excitotoxicity; apoptosis; necrosis; nuclear fragmentation; TUNEL; ATP Neuronal function and survival depend on a continuous supply of glucose and oxygen, used to generate ATP through glycolysis and mitochondrial respiration. A perturbation in energy metabolism during conditions such as ischemia, stroke, and brain trauma may cause irreversible neuronal injury. An age-related decline in energy metabolism also may contribute to neuronal loss during normal aging, as well as in neurodegenerative diseases (Wallace, 1994;Beal, 1995).There are discrepancies in the findings regarding the mechanisms of neuronal cell death after metabolic impairment. A large body of evidence supports the "secondary excitotoxicity" hypothesis that a loss of ATP leads to membrane depolarization, removal of the voltage-dependent Mg 2ϩ block of the NMDA receptor, and subsequent activation of NMDA receptor (for review, see Beal, 1992). Both in vivo and in vitro studies have shown that metabolic inhibitors potentiate glutamate and NMDA toxicity (Weller and

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Section: Discussionmentioning

confidence: 94%

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

1997

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“…Glutamate is an endogenous excitatory neurotransmitter and high concentration of glutamate induced the cell death due to oxidative stress (Choi, 1988; Fukui et al ., 2009). Glutamate excitotoxicity results in calcium ion (Ca 2+ ) influx, mitochondrial dysfunction, and elevation of ROS level and depletion of antioxidant defense system including glutathione (GSH) and glutathione reductase (GR) by inhibition of cystine uptake (Choi, 1985; Murphy et al ., 1989; Tan et al ., 1998a). Expression of Bcl-2 family of protein and caspase is also associated with neuronal cell death.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Steamed and Fermented Codonopsis lanceolata

Weon

Yun

Lee

et al. 2014

Biomolecules & Therapeutics

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Codonopsis lanceolata has been used as an herbal medicine for several lung inflammatory diseases, such as asthma, tonsillitis, and pharyngitis. Previously, we showed the neuroprotective effect of steamed and fermented C. lanceolata (SFC) in vitro and in vivo. In the current study, the treatment of HT22 cells with SFC decreased glutamate-induced cell death, suggesting that SFC protected HT22 cells from glutamate-induced cytotoxicity. Based on these, we sought to elucidate the mechanisms of the neuro-protective effect of SFC by measuring the oxidative stress parameters and the expression of Bax and caspase-3 in HT22 cells. SFC reduced contents of ROS, Ca2+ and NO. Moreover, SFC restored contents of glutathione and glutathione reductase as well as inhibited Bax and caspase-3 activity in HT22 cells. These results indicate that steamed and fermented C. lanceolata (SFC) extract protected HT22 cells by anti-oxidative effect and inhibition of the expression of Bax and caspase-3.

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“…Elevated external glutamate can cause this transporter to 'reverse' and internalize glutamate while releasing intracellular cystine. 83,84 The decreased levels of cystine result in a reduced availability of GSH for scavenging ROS produced during HI, further sensitizing OPCs. Thus, the death of immature OLs via excitotoxic and oxidative stress mechanisms greatly contributes to the pathology of PWMI.…”

Section: Ols and Diseasementioning

confidence: 99%

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

2008

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Apoptosis plays a crucial role in brain development by ensuring that only appropriately growing, migrating, and synapse-forming neurons and their associated glial cells survive. This process involves an intimate relationship between cell-cell interactions and developmental cues and is further impacted by environmental stress during neurogenesis and disease. Oligodendrocytes (OLs), the major myelin-forming cells in the central nervous system, largely form after this wave of neurogenesis but also show a selective vulnerability to cell death stimuli depending on their stage of development. This can affect not only embryonic and early postnatal brain formation but also the response to demyelinating pathologies. In the present review, we discuss the stagespecific sensitivity of OL lineage cells to damage-induced death and how this might impact myelin survival and regeneration during injury or disease. Apoptosis is a major form of programmed cell death required for the normal development of metazoan tissues, including the brain. 1 During embryonic development of the brain, many more cells than ultimately needed are generated and then selection occurs, resulting in the apoptotic depletion of the surplus cells. The importance of the apoptotic pathway in early brain development has been demonstrated by the targeted deletion in mice of the death-specific cysteine proteases caspase-3 or caspase-9, or of the co-activator Apaf-1, all of which cause severe brain overgrowth and perinatal death. 2,3 In the adult brain, 90% of the cells belong to the glial lineage, which includes oligodendrocytes (OLs), astrocytes and microglia. The glia ensures proper development, function and repair of the neuronal network. This is possible through continuous cross-talk between the glia and neurons mediated by neurotransmitters, cytokines, growth and trophic factor secretion and signaling in a reciprocal manner. [4][5][6][7] In the central nervous system (CNS), OLs are responsible for axon myelination, which insulates the electrical signals transmitted between neurons. OL and neuron development is tightly regulated and the myelin sheath is constructed only when OLs reach maturity and neurons have grown appropriately. In response to injury or during the course of neurological diseases, the neuron-glia network can be replenished to some extent but the degree of repair is dependent on the developmental stage of the OL. This complexity is compounded by the differential sensitivity of OL lineage cells to apoptotic stimuli. In the present review, we will first briefly examine the stages of differentiation of OL cells and then discuss several diseases that are impacted by OL apoptosis, noting how the stage of cell differentiation governs the sensitivity to apoptosis. Defined Stages of OL DevelopmentOligodendrocyte development can be divided into four distinct stages according to the temporal expression of cell surface markers and morphology (Table 1). 8 In the first stage, OL progenitor cells (OPCs) originate from the neuroepithelium of the ventricul...

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Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress

Cited by 939 publications

References 46 publications

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

Neuroprotective Effect of Steamed and Fermented Codonopsis lanceolata

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

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