Delayed application of aurintricarboxylic acid reduces glutamate‐induced cortical neuronal injury

Csernansky, Cynthia A.; Canzoniero, Lorella M.T.; Sensi, Stefano L.; Yu, Shan Ping; Choi, Dennis W.

doi:10.1002/jnr.490380113

Cited by 51 publications

(13 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There has been a long-standing, primarily implicit assumption that such trauma-induced spinal cord cell death, like the death of brain cells induced by several acute insults, represents the form of death called "necrosis" (Kerr et al, 1972;Balentine, 1978a,b;Selina et al, 1989). This assumption is consistent with the more recent implication of excitotoxicity in the pathogenesis of traumatic spinal cord damage (Faden and Simon, 1988;Panter et al, 1990;Wrathall et al, 1992), because excitotoxicity is typically marked by early neuronal cell swelling (Coyle et al, 1981) and likely leads preferentially to necrosis (Csernansky et al, 1994;G wag et al, 1996).…”

supporting

confidence: 79%

Neuronal and Glial Apoptosis after Traumatic Spinal Cord Injury

et al. 1997

View full text Add to dashboard Cite

Cell death was examined by studying the spinal cords of rats subjected to traumatic insults of mild to moderate severity. Within minutes after mild weight drop impact (a 10 gm weight falling 6.25 mm), neurons in the immediate impact area showed a loss of cytoplasmic Nissl substances. Over the next 7 d, this lesion area expanded and cavitated. Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive neurons were noted primarily restricted to the gross lesion area 4-24 hr after injury, with a maximum presence at 8 hr after injury. TUNEL-positive glia were present at all stages studied between 4 hr and 14 d, with a maximum presence within the lesion area 24 hr after injury. However 7 d after injury, a second wave of TUNEL-positive glial cells was noted in the white matter peripheral to the lesion and extending at least several millimeters away from the lesion center. The suggestion of apoptosis was supported by electron microscopy, as well as by nuclear staining with Hoechst 33342 dye, and by examination of DNA prepared from the lesion site. Furthermore, repeated intraperitoneal injections of cycloheximide, beginning immediately after a 12.5 mm weight drop insult, produced a substantial reduction in histological evidence of cord damage and in motor dysfunction assessed 4 weeks later. Present data support the hypothesis that apoptosis dependent on active protein synthesis contributes to the neuronal and glial cell death, as well as to the neurological dysfunction, induced by mild-to-moderate severity traumatic insults to the rat spinal cord.

show abstract

supporting

confidence: 79%

Neuronal and Glial Apoptosis after Traumatic Spinal Cord Injury

et al. 1997

View full text Add to dashboard Cite

show abstract

“…NMDAR-mediated neurotoxicity is strictly associated with the increase in cytosolic calcium level ([Ca 2? ] c ) [36,37] and enhanced ROS production [38]. Interestingly, in the present study, the staurosporine-induced enhancement in [Ca 2? ]…”

Section: Discussionmentioning

confidence: 65%

An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons

et al. 2009

View full text Add to dashboard Cite

Memantine, a clinically used NMDA receptor antagonist possesses neuroprotective properties, but the exact mechanisms of its beneficial action on neuronal survival are poorly recognized. In the present study, some intracellular mechanisms of memantine effects on staurosporine-evoked cell death were investigated in primary cortical neurons. Memantine (0.1-2 muM) suppressed neuronal apoptosis evoked by staurosporine in 7 DIV cortical neurons, whereas other antagonists of NMDA receptor, MK-801 (1 muM) and AP-5 (100 muM) were ineffective. The anti-apoptotic effects of memantine were not connected with any changes in cytoplasmic calcium concentration or reactive oxygen species level. The immunoblot analysis showed that the staurosporine induced a decrease in p-Akt protein kinase level and that this effect was reversed by memantine treatment. Moreover, the PI3-K inhibitors, wortmannin and LY 294002 attenuated the anti-apoptotic action of memantine on staurosporine-induced cell damage. Furthermore, the ELISA studies showed increased cellular and released BDNF protein level after combined treatment with memantine and staurosporine. There was no effect of memantine on the activation and expression of other protein kinases involved in the mechanism of cellular survival, i.e. ERK1/2, JNK and GSK3-beta. The obtained data suggest an NMDAR-independent action of memantine in attenuation of neuronal apoptosis and point to the engagement of BDNF and PI3-K/Akt pathway in these processes.

show abstract

“…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). Making the issue more complicated are reports that glutamate-induced cell death could be either apoptotic or necrotic depending on the intensity of stimuli or the ability of neurons to recover mitochondrial membrane potential .…”

Section: Discussionmentioning

confidence: 99%

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

1997

View full text Add to dashboard Cite

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

show abstract

Delayed application of aurintricarboxylic acid reduces glutamate‐induced cortical neuronal injury

Cited by 51 publications

References 29 publications

Neuronal and Glial Apoptosis after Traumatic Spinal Cord Injury

Neuronal and Glial Apoptosis after Traumatic Spinal Cord Injury

An involvement of BDNF and PI3-K/Akt in the anti-apoptotic effect of memantine on staurosporine-evoked cell death in primary cortical neurons

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

Contact Info

Product

Resources

About