scholarly journals Mechanism of Acute Ischemic Injury of Oligodendroglia in Early Myelinating White Matter: The Importance of Astrocyte Injury and Glutamate Release

2004 ◽  
Vol 63 (8) ◽  
pp. 872-881 ◽  
Author(s):  
Scott Wilke ◽  
Robert Thomas ◽  
Natalie Allcock ◽  
Robert Fern
Keyword(s):  
White Matter ◽  
Glutamate Release ◽  
Ischemic Injury

scholarly journals Excitotoxic Mechanisms of Ischemic Injury in Myelinated White Matter

2007 ◽  
Vol 27 (9) ◽  
pp. 1540-1552 ◽  
Author(s):  
Selva Baltan Tekkök ◽  
ZuCheng Ye ◽  
Bruce R Ransom
Keyword(s):  
White Matter ◽  
High Performance ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Kainate Receptors ◽  
Adult Mice ◽  
Direct Exposure ◽  
Glutamate Receptor Agonist

Axonal injury and dysfunction in white matter (WM) are caused by many neurologic diseases including ischemia. We characterized ischemic injury and the role of glutamate-mediated excitotoxicity in a purely myelinated WM tract, the mouse optic nerve (MON). For the first time, excitotoxic WM injury was directly correlated with glutamate release. Oxygen and glucose deprivation (OGD) caused duration-dependent loss of axon function in optic nerves from young adult mice. Protection of axon function required blockade of both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors, or removal of extracellular Ca2+. Blockade of N-methyl-D-aspartate receptors did not preserve axon function. Curiously, even extended periods of direct exposure to glutamate or kainate or AMPA failed to induce axon dysfunction. Brief periods of OGD, however, caused glutamate receptor agonist exposure to become toxic, suggesting that ionic disruption enabled excitotoxic injury. Glutamate release, directly measured using quantitative high-performance liquid chromatography, occurred late during a 60-mins period of OGD and was due to reversal of the glutamate transporter. Brief periods of OGD (i.e., 15 mins) did not cause glutamate release and produced minimal injury. These results suggested that toxic glutamate accumulation during OGD followed the initial ionic changes mediating early loss of excitability. The onset of glutamate release was an important threshold event for irreversible ischemic injury. Regional differences appear to exist in the specific glutamate receptors that mediate WM ischemic injury. Therapy for ischemic WM injury must be designed accordingly.

scholarly journals Limiting Ischemic Injury by Inhibition of Excitatory Amino Acid Release

1993 ◽  
Vol 13 (1) ◽  
pp. 88-97 ◽  
Author(s):  
Steven H. Graham ◽  
Jun Chen ◽  
Frank R. Sharp ◽  
Roger P. Simon
Keyword(s):  
Excitatory Amino Acid ◽  
Glutamate Release ◽  
Ischemic Injury ◽  
Retrosplenial Cortex ◽  
Mca Occlusion ◽  
Alternative Approach ◽  
Proximal Middle Cerebral Artery ◽  
Human Use ◽  
Unacceptable Toxicity

Excitatory amino acids (EAAs) are important mediators of ischemic injury in stroke. N-Methyl-d-aspartate (NMDA) receptor antagonists have been shown to be very effective neuroprotective agents in animal models of stroke, but may have unacceptable toxicity for human use. An alternative approach is to inhibit the release of EAAs during stroke. BW1003C87 [5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine], a drug that inhibits veratrine-induced release of the EAA glutamate in vitro, was tested in a rat model of proximal middle cerebral artery (MCA) occlusion. BW1003C87 significantly decreased ischemia-induced glutamate release in brain when given either 5 min before or 15 min following permanent MCA occlusion. Pretreated and posttreated rats had smaller infarct volumes and preserved glucose metabolism in the ischemic cortex at 24 h after MCA occlusion. BW1003C87 did not induce heat shock protein in the cingulate or retrosplenial cortex, suggesting that it does not injure neurons in these regions as do NMDA antagonists. These results demonstrate that drugs that inhibit glutamate release in ischemia may be nontoxic and show promise for the treatment of stroke.

CK2 inhibition protects white matter from ischemic injury

2018 ◽  
Vol 687 ◽  
pp. 37-42 ◽  
Author(s):  
Selva Baltan ◽  
Chinthasagar Bastian ◽  
John Quinn ◽  
Danielle Aquila ◽  
Andrew McCray ◽  
...  
Keyword(s):  
White Matter ◽  
Ischemic Injury

scholarly journals Differential Progression of Magnetization Transfer Imaging Changes Depending on Severity of Cerebral Hypoxic-Ischemic Injury

2008 ◽  
Vol 28 (9) ◽  
pp. 1613-1623 ◽  
Author(s):  
Ursula I Tuor ◽  
Shuzhen Meng ◽  
Min Qiao ◽  
Nicole B Webster ◽  
Shauna M Crowley ◽  
...  
Keyword(s):  
White Matter ◽  
Magnetization Transfer ◽  
Ischemic Injury ◽  
Subcortical White Matter ◽  
Cerebral Injury ◽  
Magnetization Transfer Ratio ◽  
Magnetization Transfer Imaging ◽  
Cerebral Hypoxia ◽  
Hypoxia Ischemia ◽  
Hypoxic Ischemic Injury

We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive for detecting cerebral ischemic injury in white matter of neonatal brain. We compared the progression of changes in T2 and the MT ratio (MTR) after cerebral hypoxic-ischemic insults of differing severity in neonatal rats. Magnetization transfer imaging parameters were first optimized, and then MTR and T2 maps were acquired at various times after a mild (rather selective white matter) or substantial insult produced by unilateral cerebral hypoxia—ischemia. Depending on insult severity, time after insult, and region (e.g., subcortical white matter or cortex), cerebral hypoxia—ischemia produced reductions in MTR and an increase in T2. The exception was acutely at 1 to 5 h at which time points MTR was reduced ipsilaterally in white matter, whereas T2 was not affected significantly. Progression of imaging changes differed in rats grouped according to whether gross damage was present after chronic recovery. Behavioral changes were generally associated with chronic reductions in MTR and gross brain damage. Magnetization transfer imaging was capable of early detection of hypoxic-ischemic injury and particularly sensitive for identifying the progression of cerebral injury in white matter. Magnetization transfer ratio has potential for assisting with early diagnosis and treatment assessment for infants affected by perinatal hypoxia—ischemia.

scholarly journals The Mechanisms of Acute Ischemic Injury in the Cell Processes of Developing White Matter Astrocytes

2007 ◽  
Vol 28 (3) ◽  
pp. 588-601 ◽  
Author(s):  
Michael G Salter ◽  
Robert Fern
Keyword(s):  
White Matter ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Complete Protection ◽  
Cell Processes ◽  
The Central Nervous System ◽  
Ion Influx ◽  
Disulphonic Acid ◽  
Process Loss

Astrocytes are fundamentally important to the maintenance and proper functioning of the central nervous system. During the period of development when myelination is occurring, white matter astrocytes are particularly sensitive to ischemic injury and their failure to regulate glutamate during ischemic conditions may be an important factor in excitotoxic injury. Here, we have identified key mechanisms of injury that operate on the processes of immature white matter astrocytes during oxygen-glucose deprivation (OGD) using GFAP-GFP mice. Oxygen-glucose deprivation produced a parallel loss of astrocyte processes and somata, assessed by both the retention of GFP fluorescence within these structures and by quantitative electron microscopy. Oxygen-glucose deprivation-induced process loss was Ca2+ independent and had two distinct mechanisms. Substituting either extracellular Na+ or Cl−, or perfusion with the Na—K–Cl co-transport blocker bumetanide, provided protection up to 40 mins of OGD but not beyond that point. HCO−3 substitution or perfusion with 4,4′-diisothiocyanostilbene-2,2′-disulphonic acid provided complete protection of the processes up to 60 mins of OGD. Zero-Na+/zero-K+ conditions provided complete protection from OGD-induced injury of processes and somata at all time points. We conclude that acute ischemic-type injury of immature astrocytes follows a cytotoxic ion influx mediated in part by Na—K–Cl co-transport and in part by Na+- and K+-dependent HCO−3 transport, a mechanism that is common to both cell processes and somata. This work provides a basis on which preventative strategies may be developed to protect white matter astrocytes from ischemic injury in susceptible individuals.

Sign in / Sign up

Export Citation Format

Share Document