Mature myelin basic protein‐expressing oligodendrocytes are insensitive to kainate toxicity

Rosenberg, Paul A.; Dai, Weimin; Gan, Xiao; Ali, Sanjida; Fu, Jennifer; Back, Stephen A.; Sánchez, Raúl Hernández; Segal, Michael M.; Follett, Pamela L.; Jensen, Frances E.; Volpe, Joseph J.

doi:10.1002/jnr.10472

Cited by 124 publications

(107 citation statements)

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“…This study used the oligodendroglial cell line OLN-93 (Richter-Landsberg and Heinrich, 1996). Previously studied examples of maturation-dependent toxicity in OLs have not been found to be caspase dependent (Back et al, 1998;Rosenberg et al, 2003;Baud et al, 2004b). The goal of the present study was to examine whether this maturation and caspasedependent vulnerability could also be observed in primary OLs and also to characterize the oxidative stress that is involved upstream of the apoptotic pathway.…”

Section: Discussionmentioning

confidence: 87%

Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter

Gerstner

DeSilva²,

Genz³

et al. 2008

J. Neurosci.

160

145

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Periventricular leukomalacia is the predominant injury in the preterm infant leading to cerebral palsy. Oxygen exposure may be an additional cause of brain injury in these infants. In this study, we investigated pathways of maturation-dependent oligodendrocyte (OL) death induced by hyperoxia in vitro and in vivo. Developing and mature OLs were subjected to 80% oxygen (0 -24 h). Lactate dehydrogenase (LDH) assay was used to assess cell viability. Furthermore, 3-, 6-, and 10-d-old rat pups were subjected to 80% oxygen (24 h), and their brains were processed for myelin basic protein staining. Significant cell death was detected after 6 -24 h incubation in 80% oxygen in pre-OLs (O4ϩ,O1Ϫ), but not in mature OLs (MBPϩ). Cell death was executed by a caspase-dependent apoptotic pathway and could be blocked by the pan-caspase inhibitor zVAD-fmk. Overexpression of BCL2 (Homo sapiens B-cell chronic lymphocytic leukemia/lymphoma 2) significantly reduced apoptosis. Accumulation of superoxide and generation of reactive oxygen species (ROS) were detected after 2 h of oxygen exposure. Lipoxygenase inhibitors 2,3,5-trimethyl-6-(12-hydroxy-5-10-dodecadiynyl-1,4-benzoquinone and N-benzyl-N-hydroxy-5-phenylpentamide fully protected the cells from oxidative injury. Overexpression of superoxide dismutase (SOD1) dramatically increased injury to pre-OLs but not to mature OLs. We extended these studies by testing the effects of hyperoxia on neonatal white matter. Postnatal day 3 (P3) and P6 rats, but not P10 pups, showed bilateral reduction in MBP (myelin basic protein) expression with 24 h exposure to 80% oxygen. Hyperoxia causes oxidative stress and triggers maturation-dependent apoptosis in pre-OLs, which involves the generation of ROS and caspase activation, and leads to white matter injury in the neonatal rat brain. These observations may be relevant to white matter injury observed in premature infants.

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Section: Discussionmentioning

confidence: 87%

Hyperoxia Causes Maturation-Dependent Cell Death in the Developing White Matter

Gerstner

DeSilva²,

Genz³

et al. 2008

J. Neurosci.

160

145

View full text Add to dashboard Cite

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“…Radioactivity of the whole-cell lysate was counted by liquid scintillation. Electrophysiological recordings on pre-OLs were performed using conventional patch-clamp techniques in whole-cell mode as published previously (Dai et al, 2001;Rosenberg et al, 2003). Kainate (100 or 300 M) and topiramate (50 or 100 M; 20 min preincubation) were applied through a gravity perfusion system.…”

Section: Methodsmentioning

confidence: 99%

“…In vitro studies have demonstrated that pre-OLs are more vulnerable to injury than mature OLs under conditions of oxidative stress , oxygen-glucose deprivation (OGD) (Fern and Moller, 2000;Yoshioka et al, 2000;Deng et al, 2003), and glutamate receptor (GluR)-mediated excitotoxicity (Itoh et al, 2002;Rosenberg et al, 2003). Glutamate accumulates in brain under hypoxic-ischemic conditions (Benveniste et al, 1984;Andine et al, 1991;Hagberg, 1992), and excessive activation of GluRs on neurons is a major mechanism in hypoxic-ischemic neuronal death (Choi, 1992;Hagberg et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

“…Rodent pre-OLs express ionotropic GluRs of the AMPA and kainate but not the NMDA subtypes (Gallo et al, 1994;Patneau et al, 1994;. AMPA-kainate receptor antagonists or OGD induces Ca 2ϩ -mediated excitotoxicity in pre-OLs more readily than in mature OLs (Fern and Moller, 2000;Yoshioka et al, 2000;Deng et al, 2003), and this increased vulnerability correlates with transient overexpression of GluRs in pre-OLs compared with mature OLs, both in vitro (Itoh et al, 2002;Rosenberg et al, 2003) and in vivo (Ong et al, 1996;Follett et al, 2000). Furthermore, in a rat model of PVL, white matter injury after unilateral carotid ligation (UCL) and hypoxia can be attenuated by systemic posttreatment with the AMPA-kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX) (Follett et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Glutamate Receptor-Mediated Oligodendrocyte Toxicity in Periventricular Leukomalacia: A Protective Role for Topiramate

et al. 2004

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Periventricular leukomalacia is a form of hypoxic-ischemic cerebral white matter injury seen most commonly in premature infants and is the major antecedent of cerebral palsy. Glutamate receptor-mediated excitotoxicity is a predominant mechanism of hypoxic-ischemic injury to developing cerebral white matter. We have demonstrated previously the protective effect of AMPA-kainate-type glutamate receptor blockade in a rodent model of periventricular leukomalacia. The present study explores the therapeutic potential of glutamate receptor blockade for hypoxic-ischemic white matter injury. We demonstrate that AMPA receptors are expressed on developing human oligodendrocytes that populate fetal white matter at 23-32 weeks gestation, the period of highest risk for periventricular leukomalacia. We show that the clinically available anticonvulsant topiramate, when administered post-insult in vivo, is protective against selective hypoxic-ischemic white matter injury and decreases the subsequent neuromotor deficits. We further demonstrate that topiramate attenuates AMPA-kainate receptor-mediated cell death and calcium influx, as well as kainate-evoked currents in developing oligodendrocytes, similar to the AMPA-kainate receptor antagonist 6-nitro-7-sulfamoylbenzo-(f)quinoxaline-2,3-dione (NBQX). Notably, protective doses of NBQX and topiramate do not affect normal maturation and proliferation of oligodendrocytes either in vivo or in vitro. Taken together, these results suggest that AMPA-kainate receptor blockade may have potential for translation as a therapeutic strategy for periventricular leukomalacia and that the mechanism of protective efficacy of topiramate is caused at least in part by attenuation of excitotoxic injury to premyelinating oligodendrocytes in developing white matter.

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“…After this, membranes were rinsed three times for 15 min with TBST and then incubated for 1 h at 20°C with horseradish peroxidase-conjugated antimouse IgG secondary antibody (Jackson ImmunoResearch, West Grove, PA) at a concentration of 1:3000. Blots were again rinsed three times for 15 min each (Rosenberg et al, 2003).…”

Section: Methodsmentioning

confidence: 99%