Anoxic injury of CNS white matter

Ransom, Bruce R.; Waxman, Stephen G.; Davis, Peter K.

doi:10.1212/wnl.40.9.1399

Cited by 69 publications

(26 citation statements)

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“…Previous studies on WM from young adult animals have failed to detect any benefit of NMDA receptor blockade on WM injury because of anoxia (Ransom et al, 1990) (Li et al, 1999). We confirmed that the NR1 functional subunit was detected in MONs at each age group (Fig.…”

Section: Nmda Receptors Do Not Protect Against Ogd-induced Injury In supporting

confidence: 83%

White Matter Vulnerability to Ischemic Injury Increases with Age Because of Enhanced Excitotoxicity

Baltan¹,

Besancon

Mbow³

et al. 2008

J. Neurosci.

116

182

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Stroke incidence increases with age and this has been attributed to vascular factors. We show here that CNS white matter (WM) is intrinsically more vulnerable to ischemic injury in older animals and that the mechanisms of WM injury change as a function of age. The mouse optic nerve was used to study WM function. WM function in older animals (12 months) was not protected from ischemic injury by removal of extracellular Ca 2ϩ or by blockade of reverse Na ϩ /Ca 2ϩ exchange, as is the case with young adults. Ischemic WM injury in older mice is predominately mediated by glutamate release and activation of AMPA/kainate-type glutamate receptors. Glutamate release, attributable to reverse glutamate transport, occurs earlier and is more robust in older mice that show greater expression of the glutamate transporter. The observation that WM vulnerability to ischemic injury is age dependent has possible implications for the pathogenesis of other age-related CNS conditions.

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Section: Nmda Receptors Do Not Protect Against Ogd-induced Injury In supporting

confidence: 83%

White Matter Vulnerability to Ischemic Injury Increases with Age Because of Enhanced Excitotoxicity

Baltan¹,

Besancon

Mbow³

et al. 2008

J. Neurosci.

116

182

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“…8 The protective effect of ketamine, an NMDA receptor antagonist, on anoxic optic nerve was previously reported and was supposed to be related to its blocking voltage-gated Na ϩ channels. 19 Interestingly, an NMDA receptor antagonist was demonstrated to protect the spinal cord from ischemic injury. 20 It is not known whether the NMDA antagonist…”

Section: Discussionmentioning

confidence: 99%

The N -Methyl- d -Aspartate Antagonist CNS 1102 Protects Cerebral Gray and White Matter From Ischemic Injury Following Temporary Focal Ischemia in Rats

Schäbitz

Fisher

2000

Stroke

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Background and Purpose-Cerebral white matter is as sensitive as gray matter to ischemic injury and is probably amenable to pharmacological intervention. In this study we investigated whether an N-methyl-D-aspartate (NMDA) antagonist, CNS 1102, protects not only cerebral gray matter but also white matter from ischemic injury. Methods-Ten rats underwent 15 minutes of temporary focal ischemia and were blindly assigned to CNS 1102 intravenous bolus injection (1.13 mg/kg) followed by intravenous infusion (0.33 mg/kg per hour) for 3.75 hours or to vehicle (nϭ5 per group) immediately after reperfusion. Seventy-two hours after ischemia, the animals were perfusion fixed for histology. The severity of neuronal necrosis in the cortex and striatum was semiquantitatively analyzed. The Luxol fast blue-periodic acid Schiff stain and Bielschowsky's silver stain were used to measure optical densities (ODs) of myelin and axons, respectively, in the internal capsule of both hemispheres, and the OD ratio was calculated to reflect the severity of white matter damage. Results-Neuronal damage in both the cortex and the striatum was significantly better in the drug-treated group than in the placebo group (PϽ0.05). The OD ratio of both the axons (0.93Ϯ0.08 versus 0.61Ϯ0.18; PϽ0.01) and the myelin sheath (0.95Ϯ0.07 versus 0.67Ϯ0.19; Pϭ0.01) was significantly higher in the CNS 1102 group than in the placebo group. The neurological score was significantly improved in the drug-treated group (PϽ0.05). Conclusions-The NMDA receptor antagonist CNS 1102 protects not only cerebral gray matter but also white matter from ischemic injury, most probably by preventing degeneration of white matter structures such as myelin and axons. (Stroke.

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“…A preparation of rat optic nerve has been used to study the effects of anoxia in vitro (Ransom et al, 1990b;Stys et al, 1990Stys et al, , 1991a. The results indicate that Ca 2ϩ influx into axons leads to irreversible damage.…”

Section: Abstract: Rat; Spinal Cord Injury; Sodium Channel; Tetrodotmentioning

confidence: 99%

Local Blockade of Sodium Channels by Tetrodotoxin Ameliorates Tissue Loss and Long-Term Functional Deficits Resulting from Experimental Spinal Cord Injury

1997

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Although relatively little is known of the mechanisms involved in secondary axonal loss after spinal cord injury (SCI), recent data from in vitro models of white matter (WM) injury have implicated abnormal sodium influx as a key event. We hypothesized that blockade of sodium channels after SCI would reduce WM loss and long-term functional deficits. To test this hypothesis, a sufficient and safe dose (0.15 nmol) of the potent Na ϩ channel blocker tetrodotoxin (TTX) was determined through a doseresponse study. We microinjected TTX or vehicle (VEH) into the injury site at 15 min after a standardized contusive SCI in the rat. Behavioral tests were performed 1 d after injury and weekly thereafter. Quantitative histopathology at 8 weeks postinjury showed that TTX treatment significantly reduced tissue loss at the injury site, with greater effect on sparing of WM than gray matter. TTX did not change the pattern of chronic histopathology typical of this SCI model, but restricted its extent, tripled the area of residual WM at the epicenter, and reduced the average length of the lesions. Serotonin immunoreactivity caudal to the epicenter, a marker for descending motor control axons, was nearly threefold that of VEH controls. The increase in WM at the epicenter was significantly correlated with the decrease in functional deficits. The TTX group exhibited a significantly enhanced recovery of coordinated hindlimb functions, more normal hindlimb reflexes, and earlier establishment of a reflex bladder. The results demonstrate that Na ϩ channels play a critical role in WM loss in vivo after SCI.

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Anoxic injury of CNS white matter

Cited by 69 publications

References 0 publications

White Matter Vulnerability to Ischemic Injury Increases with Age Because of Enhanced Excitotoxicity

White Matter Vulnerability to Ischemic Injury Increases with Age Because of Enhanced Excitotoxicity

The N -Methyl- d -Aspartate Antagonist CNS 1102 Protects Cerebral Gray and White Matter From Ischemic Injury Following Temporary Focal Ischemia in Rats

Local Blockade of Sodium Channels by Tetrodotoxin Ameliorates Tissue Loss and Long-Term Functional Deficits Resulting from Experimental Spinal Cord Injury

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