Excitotoxic Mechanisms of Ischemic Injury in Myelinated White Matter

Abstract

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 a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors, or removal of extracellular Ca 2 + . 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 highperformance 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.

Tissue Oxygen is Reduced in White Matter of Spontaneously Hypertensive-Stroke Prone Rats: A Longitudinal Study with Electron Paramagnetic Resonance

“…Untreated SHR/SP showed a similar increase in pO 2 at 12 weeks, but had less of a decrease at 13 weeks and remained alive. The continued decrease in pO 2 in the JPD/UCAO group was associated with vascular damage and death by 16 weeks, which contrasted with the normal histology in the untreated rats in spite of the decrease in pO 2 .…”

“…Electron paramagnetic resonance oximetry measurements obtained at 6 to 8 weeks were consistent with pO 2 values obtained from WKY rats and the literature. [21][22][23] At 9 weeks of age, a gradual increase in WM pO 2 was observed that continued to rise weekly up to 12 weeks of age. At age week 12, a significant 32% increase in pO 2 in the WM of SHR/SP rats was observed compared with baseline measurements at age weeks 6 to 8 as shown in Figure 3A.…”

“…To assess whether SHR/SP with or without JPD/UCAO treatment would spontaneously develop neuropathologic lesions and vascular morphologic changes in WM, and their correlation with the changes in WM pO 2 shown by EPR analysis, H&E staining of the brain sections of the SHR/SP animals was conducted, and WKY rats at age 12 weeks were used as a normal animal control. The rats, which were used for histopathologic assessment of tissue and vascular damage, were not subjected to EPR measurement.…”

“…[9][10][11] Surprisingly, in light of the high significance of O 2 in brain physiology, O 2 measurement in the WM, and specifically related to VCI and WM injury has not been measured or explored in vivo although both conditions have been associated with stroke or transient ischemic attack and the diffuse pattern of injury is highly suggestive of a hypoxic injury. 2,7,[12][13][14] Direct measurement of O 2 level in tissues as the partial pressure of oxygen (pO 2 ) in the brain is one of the most important variables in many physiologic, pathologic, and therapeutic processes. [15][16][17] The brain tissue is highly sensitive to changes in availability of O 2 and pathological changes can occur if there are significant changes in the delivery or utilization of O 2 in local regions of the brain.…”

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

“…Studies have confirmed perisynaptic localisation of N-methyl-D-aspartate (NMDA) receptors in RGCs [17]. Although there is evidence for the presence of non-NMDA glutaminergic receptors for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainite in the postsynaptic myelinated axons in the central neurons [18] and the expression of NMDA receptors on oligodendrocyte processes in white matter [19], there is no direct evidence of presence of functional NMDA receptors on axons [20]. Therefore, retro-orbital optic nerve axonal degeneration observed in NMDA-induced retinal insult is logically a consequence of primary damage to RGCs; however, damage to intraorbital axons can also be considered a primary site of insult, if future studies provide direct evidence for the presence of functional NMDA receptors over axons.…”