The pathophysiology of anoxic injury in mammalian central white matter

Ransom, B R; Waxman, S. G.; Stys, Peter K.

doi:10.1016/0022-510x(91)90237-2

Cited by 17 publications

(18 citation statements)

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“…We suggest that the irreversible functional and anatomic damage seen in in vivo and other in vitro ischemic injuries is mainly due to secondary injury mechanisms or is influenced by adjacent gray matter (15,16,29,32,35).…”

Section: Isolated Guinea Pig Spinal Cord Ischemic Modelmentioning

confidence: 89%

Resistance of isolated mammalian spinal cord white matter to oxygen-glucose deprivation

Peasley

Shi

2002

American Journal of Physiology-Cell Physiology

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Peasley, Melissa A., and Riyi Shi. Resistance of isolated mammalian spinal cord white matter to oxygen-glucose deprivation. Am J Physiol Cell Physiol 283: C980-C989, 2002. First published May 22, 2002 10.1152/ajpcell.00591.2001We found that isolated guinea pig spinal cord white matter is resistant to acute oxygen-glucose deprivation. Sixty minutes of oxygen-glucose deprivation resulted in a 60% reduction of compound action potential (CAP) conductance, and there was a near complete recovery after 60 min reperfusion. Corresponding horseradish peroxidase-exclusion assay showed little axonal membrane damage. To further deprive the axons of metabolic substrate, we added 2 mM sodium cyanide or 2 mM sodium azide, both mitochondrial suppressors, to the ischemic medium, which completely abolished CAP and resulted in a 15 to ϳ30% recovery postreperfusion. Both compounds preferentially reduced the conductance of large diameter axons. We suggest the residual ATP in our ischemic model can protect anatomic integrity and physiological functioning of spinal axons following ischemic insult. This further suggests that oxygen-glucose deprivation alone cannot be solely responsible for short-term functional and anatomic damage. The damaging effects of ischemia in vivo may be mediated by factors originating from the gray matter of the cord or other systemic factors; both were largely eliminated in our in vitro white matter preparation.axons; neurotrauma; reperfusion; mitochondria; membrane OXYGEN-GLUCOSE DEPRIVATION, or ischemia, can produce or exacerbate many devastating insults to the central nervous system (CNS), such as stroke and paralysis (1,21,29,31,35,36). In the case of spinal cord injury, paralysis can be a consequence of even brief ischemic episodes such as result from clamping of the aorta during life-saving surgeries (1,7,12,13,19). Furthermore, ischemia can arise secondary to physical insults when the integrity of blood vessels is compromised (20,35,36). Altogether, it is widely recognized that ischemia plays a critical role in the neuropathology of the CNS in general and the spinal cord in particular (20,29,31).Although there is little doubt that ischemia causes cellular damage, the mechanism of just how ischemia can produce such damage at the cell and tissues level of organization is not fully understood. This is because ischemia has been shown to activate many physiological and/or chemical pathways, such as prolonging neurotransmitter release, elevation of reactive oxygen species, and the increase of calcium influx due to membrane depolarization (6,16,18,35). It is possible that these secondary effectors, not oxygen-glucose deprivation alone, are the real culprits in causing cellular damage. It is also possible that there is a hierarchy of importance when each of these mechanisms acts in concert to cause cell damage, though some mechanisms may be more damaging to the cell than others. In our opinion, it is difficult to investigate these possibilities in the absence of a model where the overall condition of the cord,...

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Section: Isolated Guinea Pig Spinal Cord Ischemic Modelmentioning

confidence: 89%

Resistance of isolated mammalian spinal cord white matter to oxygen-glucose deprivation

Peasley

Shi

2002

American Journal of Physiology-Cell Physiology

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“…Tissue degeneration after SCI develops later and more slowly in WM than in gray matter (GM) (Lampert, 1967;Dohrmann et al, 1972;Balentine, 1978a,b;Ransom et al, 1990a). Furthermore, the sparing of even a small percentage of axons can significantly enhance function (Windle et al, 1958;Guth et al, 1980;Blight, 1983;Blight and Young, 1990).…”

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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“…Mg, in comparison with several other putative neuroprotectants, had previously been shown to confer white matter protection. 2 Post hoc analysis of IMAGES data indicated that the effect in subcortical stroke was greatest in patients with lacunar clinical syndrome (LACS) (odds ratio [OR] 0.70; 95% CI, 0.53 to 0.92) and confirmed a significant interaction between treatment and LACS (Pϭ0.005). 1 IMAGES also reported a significant interaction between treatment effect and baseline mean arterial blood pressure (MABP) (Pϭ0.02), with benefit in patients with a higher-than-median MABP in a post hoc analysis.…”

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confidence: 95%

Magnesium for Treatment of Acute Lacunar Stroke Syndromes

Aslanyan

Weir

Muir

et al. 2007

Stroke

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for the IMAGES Study InvestigatorsBackground and Purpose-A prespecified interaction analysis of the neutral Intravenous Magnesium Efficacy in Stroke (IMAGES) trial revealed significant benefit from magnesium (Mg) in patients with noncortical stroke. Post hoc analysis indicated that this effect was seen in lacunar clinical syndromes (LACS), interaction Pϭ0.005. We have now examined whether this interaction could be explained by confounding baseline factors. Methods-LACS was defined on the basis of neurological signs and did not include imaging. We investigated the interaction between baseline variables and Mg treatment on global outcome. We used logistic-regression models to test whether the Mg-LACS interaction remained significant after adjusting for stratification variables, sex, a novel stroke severity score, and baseline variables that had an interaction with treatment (PϽ0.1). Results-The Mg (nϭ383) and placebo (nϭ382) groups of LACS patients were well matched on baseline factors. In addition to LACS, we found an interaction between beneficial Mg treatment effect and younger age (Pϭ0.003), higher baseline diastolic blood pressure (Pϭ0.02), higher mean blood pressure (Pϭ0.02), and absence of ischemic heart disease (Pϭ0.07). Even so, the adjusted Mg-LACS interaction remained significant (odds ratio

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The pathophysiology of anoxic injury in mammalian central white matter

Cited by 17 publications

References 0 publications

Resistance of isolated mammalian spinal cord white matter to oxygen-glucose deprivation

Resistance of isolated mammalian spinal cord white matter to oxygen-glucose deprivation

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

Magnesium for Treatment of Acute Lacunar Stroke Syndromes

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