White Matter Axon Vulnerability to AMPA/Kainate Receptor-Mediated Ischemic Injury Is Developmentally Regulated

McCarran, William J.; Goldberg, Mark P.

doi:10.1523/jneurosci.5542-06.2007

Cited by 71 publications

(49 citation statements)

References 58 publications

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“…This pattern strongly suggests that these changes are a secondary consequence of delayed cell death rather than the primary cause. The present finding that EAA levels were not raised during even severe ischemia that was associated with severe white matter injury also strongly suggests that non-receptor-mediated glutamate toxicity is unlikely to make a material contribution to PVL (Rosin et al 2004;McCarran and Goldberg 2007). However, these findings do not exclude the possibility that aberrantly enhanced activation of Ca 2+ -permeable a-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptors in response to physiologic levels of glutamate in the first few hours after cerebral ischemia may contribute to evolving PVL (Deng et al 2003).…”

Section: Discussionsupporting

confidence: 58%

Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep

Fraser

Zijl

Mocatta

et al. 2008

Journal of Neurochemistry

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It is widely hypothesized that accumulation of excitatory amino acids, and oxygen free radicals during or after exposure to hypoxia–ischemia play a pivotal role in preterm periventricular white matter injury; however, there is limited evidence in the intact brain. In preterm fetal sheep (0.65 gestation; term 147 days) we found no significant increase in extracellular levels of excitatory amino acids measured by microdialysis in the periventricular white matter during cerebral ischemia induced by bilateral carotid occlusion. There was no significant change in 8‐isoprostane or malondialdehyde levels in the early phase of recovery after occlusion. In contrast, there was a significant delayed increase in most amino acids and in malondialdehyde (but not 8‐isoprostane) that was maximal approximately 2–3 days after occlusion. The increase in glutamate was significantly correlated with a secondary increase in cortical impedance, an index of cytotoxic edema, and with white matter damage 3 days post‐insult. In conclusion, no significant accumulation of cytotoxins was found within immature white matter during cerebral ischemia. Although a minority of fetuses showed a delayed increase in some cytotoxins, this occurred many days after ischemia, in association with secondary cytotoxic edema, strongly suggesting that these changes are mainly a consequence of evolving cell death.

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Section: Discussionsupporting

confidence: 58%

Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep

Fraser

Zijl

Mocatta

et al. 2008

Journal of Neurochemistry

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“…White matter injury in the immature rodent acutely results in loss of the immature OL marker O1 and the mature OL marker MBP (Follett et al, 2000;Liu et al, 2002;McCarran and Goldberg, 2007). Thus, we assessed for acute white matter injury by immunostaining for both O1 and MBP in parietal white matter of P9 rats (72 h after H/I).…”

Section: Resultsmentioning

confidence: 99%

NMDA Receptor Blockade with Memantine Attenuates White Matter Injury in a Rat Model of Periventricular Leukomalacia

Manning

Talos²,

Zhou³

et al. 2008

Journal of Neuroscience

161

130

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Hypoxia-ischemia (H/I) in the premature infant leads to white matter injury termed periventricular leukomalacia (PVL), the leading cause of subsequent neurological deficits. Glutamatergic excitotoxicity in white matter oligodendrocytes (OLs) mediated by cell surface glutamate receptors (GluRs) of the AMPA subtype has been demonstrated as one factor in this injury. Recently, it has been shown that rodent OLs also express functional NMDA GluRs (NMDARs), and overactivation of these receptors can mediate excitotoxic OL injury. Here we show that preterm human developing OLs express NMDARs during the PVL period of susceptibility, presenting a potential therapeutic target. The expression pattern mirrors that seen in the immature rat. Furthermore, the uncompetitive NMDAR antagonist memantine attenuates NMDA-evoked currents in developing OLs in situ in cerebral white matter of immature rats. Using an H/I rat model of white matter injury, we show in vivo that post-H/I treatment with memantine attenuates acute loss of the developing OL cell surface marker O1 and the mature OL marker MBP (myelin basic protein), and also prevents the long-term reduction in cerebral mantle thickness seen at postnatal day 21 in this model. These protective doses of memantine do not affect normal myelination or cortical growth. Together, these data suggest that NMDAR blockade with memantine may provide an effective pharmacological prevention of PVL in the premature infant.

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“…In PVL, the role of hypoxic-ischemic injury in the pathogenesis of the cerebral white matter damage is well-documented in animal models and human studies (10,27). Direct, primary injury to the axon in the diffuse component of PVL is thus likely due to hypoxia-ischemia based on the recognized hypoxic-ischemic insults to developing axons in animal models (28,29). The diffuse axonal damage may also reflect degeneration secondary to the death of neuronal cell bodies in the cerebral cortex and/or subcortical regions (thalamus/basal ganglia/brainstem) whose axons project to and from the cerebral cortex.…”

Section: Axonal Regeneration And/or Degeneration In Pvlmentioning

confidence: 99%

Diffuse Axonal Injury in Periventricular Leukomalacia as Determined by Apoptotic Marker Fractin

et al. 2008

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Periventricular leukomalacia (PVL), the major substrate of neurologic deficits in premature infants, is associated with reduced white matter volume. Using immunomarkers of axonal pathology [␤-amyloid precursor protein (␤-APP) and apoptotic marker fractin], we tested the hypothesis that widespread (diffuse) axonal injury occurs in the gliotic white matter beyond the foci of necrosis in PVL, thus contributing to the white matter volume reduction. In a cohort of 17 control cases and 13 PVL cases with lesions of different chronological ages, diffuse axonal damage in PVL was detected by fractin in white matter sites surrounding and distant from acute and organizing foci of necrosis. Using ␤-APP, axonal spheroids were detected within necrotic foci in the acute and organizing (subacute) stages, a finding consistent with others. Interestingly, GAP-43 expression was also detected in spheroids in the necrotic foci, suggesting attempts at axonal regeneration. Thirty-one percent of the PVL cases had thalamic damage and 15% neuronal injury in the cerebral cortex overlying PVL. We conclude that diffuse axonal injury, as determined by apoptotic marker fractin, occurs in PVL and that its cause likely includes primary ischemia and trophic degeneration secondary to corticothalamic neuronal damage. (Pediatr Res 63: 656-661, 2008)

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White Matter Axon Vulnerability to AMPA/Kainate Receptor-Mediated Ischemic Injury Is Developmentally Regulated

Cited by 71 publications

References 58 publications

Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep

Extracellular amino acids and lipid peroxidation products in periventricular white matter during and after cerebral ischemia in preterm fetal sheep

NMDA Receptor Blockade with Memantine Attenuates White Matter Injury in a Rat Model of Periventricular Leukomalacia

Diffuse Axonal Injury in Periventricular Leukomalacia as Determined by Apoptotic Marker Fractin

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