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Excitotoxic mechanisms of ischemic injury in myelinated white matter

Selva Baltan Tekkök1, ZuCheng Ye, Bruce R Ransom

  • 1Department of Neurology, Harborview Medical Center, University of Washington School of Medicine, Seattle, Washington 98104, USA. selva@u.washington.edu

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
|February 15, 2007
PubMed

Insights

Ischemic white matter injury involves glutamate excitotoxicity. Glutamate release, occurring late during oxygen-glucose deprivation, drives irreversible axonal damage, necessitating targeted therapies.

Area of Science:

  • Neuroscience
  • Neurology
  • White Matter Research

Background:

  • Axonal injury and dysfunction in white matter (WM) are implicated in numerous neurological diseases, notably ischemia.
  • Glutamate-mediated excitotoxicity is a key factor in neurological damage.
  • The mouse optic nerve (MON) serves as a model for studying purely myelinated WM tracts.

Purpose of the Study:

  • To characterize ischemic injury in the mouse optic nerve (MON).
  • To elucidate the role of glutamate-mediated excitotoxicity in ischemic WM injury.
  • To establish a direct correlation between glutamate release and excitotoxic WM injury.

Main Methods:

  • Oxygen and glucose deprivation (OGD) applied to MON to assess axon function.
  • Pharmacological blockade of glutamate receptors (AMPA, kainate, NMDA).
  • Extracellular Ca(2+) manipulation.
  • Quantitative high-performance liquid chromatography (HPLC) for direct glutamate measurement.

Main Results:

  • OGD induced duration-dependent loss of axon function in MON.
  • Protection of axon function required blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors, or Ca(2+) removal.
  • N-methyl-D-aspartate receptor blockade did not preserve axon function.
  • Glutamate release, measured by HPLC, occurred late during OGD (60 mins) due to transporter reversal.
  • Brief OGD (15 mins) caused minimal injury and no glutamate release.
  • Glutamate receptor agonist exposure was toxic only after brief OGD, indicating ionic disruption enables excitotoxicity.

Conclusions:

  • Toxic glutamate accumulation during ischemia follows initial ionic changes that impair excitability.
  • The onset of glutamate release is a critical threshold for irreversible ischemic WM injury.
  • Specific glutamate receptors mediating WM ischemic injury may vary regionally.
  • Therapeutic strategies for ischemic WM injury should consider these receptor-specific and temporal dynamics.

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