The Role of Glutamate Neurotoxicity in Hypoxic-Ischemic Neuronal Death

Choi, Dennis W.; Rothman, Steven M.

doi:10.1146/annurev.ne.13.030190.001131

Cited by 2,086 publications

(786 citation statements)

References 71 publications

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“…NMDA receptors have been implicated as a mediator of neuronal damage caused by excess glutamate in a number of neurologic disorders, including stroke, epilepsy, trauma, and neurodegenerative disorders (12,13). DeGiorgio and colleagues showed that injection of anti-NR2 glutamate receptor binding antibodies (purified antibodies from the sera of SLE patients, and 1 CSF sample from an SLE patient with progressive cognitive decline) into mouse brain resulted in apoptosis of the neuronal cells without signs of inflammation (6).…”

Section: Discussionmentioning

confidence: 99%

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

Arinuma¹,

Yanagida²,

Hirohata³

2008

Arthritis & Rheumatism

215

130

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Results. Purified anti-NR2 bound to the surface of SK-N-MC cells. Levels of anti-NR2 antibodies in CSF were significantly elevated in patients with diffuse NPSLE compared with levels in control patients or those with focal NPSLE, whereas there were no significant differences in serum anti-NR2 levels among the 3 groups. In 31 of the 38 patients with diffuse NPSLE (81.6%) and 8 of the 18 patients with focal NPSLE (44.4%), CSF anti-NR2 levels were more than 3 SD above the mean level in the control patients (P ‫؍‬ 0.0120 by chi-square test). Conclusion.These results indicate that anti-NR2 is a constituent of antineuronal antibodies and, more importantly, that anti-NR2 antibodies in CSF, but not in serum, are associated with diffuse NPSLE.

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Section: Discussionmentioning

confidence: 99%

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

Arinuma¹,

Yanagida²,

Hirohata³

2008

Arthritis & Rheumatism

215

130

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“…When the EPO molecule binds to the EPOR, a dimerization of the receptor occurs with subsequent autophosphorylation of Jak2 and receptor activation. In non-neuronal cells, Jak2 activation conducts the activation of different downstream signaling pathways like Ras/MAPK, PI(3)K and STAT5 (Choi and Rothman, 1990;Ihle et al, 1995). However, this hematopoietic Fig.…”

Section: Discussionmentioning

confidence: 99%

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

Montero

Poulsen

Noraberg

et al. 2007

Experimental Neurology

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In addition to its well-known hematopoietic effects, erythropoietin (EPO) also has neuroprotective properties. However, hematopoietic side effects are unwanted for neuroprotection, underlining the need for EPO-like compounds with selective neuroprotective actions. One such compound, devoid of hematopoietic bioactivity, is the chemically modified, EPO-derivative carbamylerythropoietin (CEPO). For comparison of the neuroprotective effects of CEPO and EPO, we subjected organotypic hippocampal slice cultures to oxygen-glucose deprivation (OGD) or N-methyl-D-aspartate (NMDA) excitotoxicity. Hippocampal slice cultures were pretreated for 24 h with 100 IU/ml EPO (= 26 nM) or 26 nM CEPO before OGD or NMDA lesioning. Exposure to EPO and CEPO continued during OGD and for the next 24 h until histology, as well as during the 24 h exposure to NMDA. Neuronal cell death was quantified by cellular uptake of propidium iodide (PI), recorded before the start of OGD and NMDA exposure and 24 h after. In cultures exposed to OGD or NMDA, CEPO reduced PI uptake by 49 ± 3 or 35 ± 8%, respectively, compared to lesion-only controls. EPO reduced PI uptake by 33 ± 5 and 15 ± 8%, respectively, in the OGD and NMDA exposed cultures. To elucidate a possible mechanism involved in EPO and CEPO neuroprotection against OGD, the integrity of α-II-spectrin cytoskeletal protein was studied. Both EPO and CEPO significantly reduced formation of spectrin cleavage products in the OGD model. We conclude that CEPO is at least as efficient neuroprotectant as EPO when excitotoxicity is modeled in mouse hippocampal slice cultures.

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“…Thereafter, released glutamate stimulates N-methyl-D-aspartate receptors leading to intracellular Ca 2 + accumulation, which is believed a major source for the increased intracellular Ca 2 + after stroke (Choi and Rothman, 1990). As we have discussed, mild and moderate hypothermia merely delays the onset of AD and intracellular Ca 2 + accumulation in global ischemia; it is unlikely that the hypothermia would completely inhibit glutamate release when AD occurs and intracellular Ca 2 + increases.…”

Section: Glutamate Releasementioning

confidence: 99%

“…A large amount of glutamate is released from the intracellular space into the extracellular space (Colbourne et al, 1997;Obrenovitch and Urenjak, 1997;Zhao et al, 1997), which stimulates N-methyl-D-aspartate receptors and leads to increased intracellular calcium levels (Choi and Rothman, 1990). Ischemia/ reperfusion generates products of reactive oxygen species in large quantities (Chan, 2001).…”

Section: Introductionmentioning

confidence: 99%

General versus Specific Actions of Mild-Moderate Hypothermia in Attenuating Cerebral Ischemic Damage

Zhao

Steinberg

Sapolsky

2007

J Cereb Blood Flow Metab

152

135

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Mild or moderate hypothermia is generally thought to block all changes in signaling events that are detrimental to ischemic brain, including ATP depletion, glutamate release, Ca 2 + mobilization, anoxic depolarization, free radical generation, inflammation, blood-brain barrier permeability, necrotic, and apoptotic pathways. However, the effects and mechanisms of hypothermia are, in fact, variable. We emphasize that, even in the laboratory, hypothermic protection is limited. In certain models of permanent focal ischemia, hypothermia may not protect at all. In cases where hypothermia reduces infarct, some studies have overemphasized its ability to maintain cerebral blood flow and ATP levels, and to prevent anoxic depolarization, glutamate release during ischemia. Instead, hypothermia may protect against ischemia by regulating cascades that occur after reperfusion, including blood-brain barrier permeability and the changes in gene and protein expressions associated with necrotic and apoptotic pathways. Hypothermia not only blocks multiple damaging cascades after stroke, but also selectively upregulates some protective genes. However, most of these mechanisms are addressed in models with intraischemic hypothermia; much less information is available in models with postischemic hypothermia. Moreover, although it has been confirmed that mild hypothermia is clinically feasible for acute focal stroke treatment, no definite beneficial effect has been reported yet. This lack of clinical protection may result from suboptimal criteria for patient entrance into clinical trials. To facilitate clinical translation, future efforts in the laboratory should focus more on the protective mechanisms of postischemic hypothermia, as well as on the effects of sex, age and rewarming during reperfusion on hypothermic protection.

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The Role of Glutamate Neurotoxicity in Hypoxic-Ischemic Neuronal Death

Cited by 2,086 publications

References 71 publications

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

Association of cerebrospinal fluid anti–NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

General versus Specific Actions of Mild-Moderate Hypothermia in Attenuating Cerebral Ischemic Damage

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