Novel Injury Mechanism in Anoxia and Trauma of Spinal Cord White Matter: Glutamate Release via Reverse Na+-dependent Glutamate Transport

Object In experimental models of spinal cord injury (SCI) researchers have typically focused on contusion and transection injuries. Clinically, however, other injury mechanisms such as fracture–dislocation and distraction also frequently occur. The objective of the present study was to compare the primary damage in three clinically relevant animal models of SCI. Methods Contusion, fracture–dislocation, and flexion–distraction animal models of SCI were developed. To visualize traumatic increases in cellular membrane permeability, fluorescein–dextran was infused into the cerebrospi-nal fluid prior to injury. High-speed injuries (approaching 100 cm/second) were produced in the cervical spine of deeply anesthetized Sprague–Dawley rats (28 SCI and eight sham treated) with a novel multimechanism SCI test system. The animals were killed immediately thereafter so that the authors could characterize the primary injury in the gray and white matter. Sections stained with H & E showed that contusion and dislocation injuries resulted in similar central damage to the gray matter vasculature whereas no overt hemorrhage was detected following distraction. Contusion resulted in membrane disruption of neuronal somata and axons localized within 1 mm of the lesion epicenter. In contrast, membrane compromise in the dislocation and distraction models was observed to extend rostrally up to 5 mm, particularly in the ventral and lateral white matter tracts. Conclusions Given the pivotal nature of hemorrhagic necrosis and plasma membrane compromise in the initiation of downstream SCI pathomechanisms, the aforementioned differences suggest the presence of mechanism-specific injury regions, which may alter future clinical treatment paradigms.

Download Full-text

Modeling Primary Blast Injury in Isolated Spinal Cord White Matter

2009 2nd International Conference on Biomedical Engineering and Informatics ◽

10.1109/bmei.2009.5305363 ◽

2009 ◽

Author(s):

Sean Connell ◽

Hui Ouyang ◽

Riyi Shi

Keyword(s):

Spinal Cord ◽

White Matter ◽

Blast Injury ◽

Primary Blast

Download Full-text

Glutamate, NMDA, and AMPA Induced Changes in Extracellular Space Volume and Tortuosity in the Rat Spinal Cord

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200109000-00005 ◽

2001 ◽

Vol 21 (9) ◽

pp. 1077-1089 ◽

Cited By ~ 23

Author(s):

Lýdia Vargová ◽

Pavla Jendelová ◽

Alexandr Chvátal ◽

Eva Syková

Keyword(s):

Spinal Cord ◽

Glutamate Receptor ◽

Extracellular Space ◽

Volume Fraction ◽

Glutamate Release ◽

Extracellular Potassium ◽

Receptor Agonists ◽

Diffusion Parameters ◽

Glutamate Receptor Agonists ◽

Cellular Swelling

Glutamate release, particularly in pathologic conditions, may result in cellular swelling. The authors studied the effects of glutamate, N-methyl-d-aspartate (NMDA), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on extracellular pH (pHe), extracellular potassium concentration ([K+]e), and changes in extracellular space (ECS) diffusion parameters (volume fraction α, tortuosity λ) resulting from cellular swelling. In the isolated spinal cord of 4-to 12-day-old rats, the application of glutamate receptor agonists induced an increase in [K+]e, alkaline-acid shifts, a substantial decrease in α, and an increase in λ. After washout of the glutamate receptor agonists, α either returned to or overshot normal values, whereas λ remained elevated. Pretreatment with 20 mmol/L Mg++, MK801, or CNQX blocked the changes in diffusion parameters, [K+]e and pHe evoked by NMDA or AMPA. However, the changes in diffusion parameters also were blocked in Ca2+-free solution, which had no effect on the [K+]e increase or acid shift. The authors conclude that increased glutamate release may produce a large, sustained and [Ca2+]e-dependent decrease in α and increase in λ. Repetitive stimulation and pathologic states resulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotoxicity and neuronal damage.

Download Full-text

Holocord involvement with sparing of the peripheral white matter rim in longitudinally extensive spinal cord lesions of neuromyelitis optica

Clinical and Experimental Neuroimmunology ◽

10.1111/cen3.12274 ◽

2015 ◽

Vol 6 (S1) ◽

pp. 78-79

Author(s):

Shotaro Hayashida ◽

Katsuhisa Masaki ◽

Takuya Matsushita ◽

Mitsuru Watanabe ◽

Ryo Yamasaki ◽

...

Keyword(s):

Spinal Cord ◽

White Matter ◽

Neuromyelitis Optica ◽

Spinal Cord Lesions

Download Full-text

Excitotoxic Mechanisms of Ischemic Injury in Myelinated White Matter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600455 ◽

2007 ◽

Vol 27 (9) ◽

pp. 1540-1552 ◽

Cited By ~ 84

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.

Download Full-text

Noninvasive diffusion tensor imaging of evolving white matter pathology in a mouse model of acute spinal cord injury

Magnetic Resonance in Medicine ◽

10.1002/mrm.21316 ◽

2007 ◽

Vol 58 (2) ◽

pp. 253-260 ◽

Cited By ~ 129

Author(s):

Joong Hee Kim ◽

David N. Loy ◽

Hsiao-Fang Liang ◽

Kathryn Trinkaus ◽

Robert E. Schmidt ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Diffusion Tensor Imaging ◽

White Matter ◽

Mouse Model ◽

Diffusion Tensor ◽

Acute Spinal Cord Injury ◽

Cord Injury ◽

White Matter Pathology

Download Full-text

Spinal cord grey matter lesions in multiple sclerosis detected by post-mortem high field MR imaging

Multiple Sclerosis Journal ◽

10.1177/1352458508096876 ◽

2008 ◽

Vol 15 (2) ◽

pp. 180-188 ◽

Cited By ~ 49

Author(s):

CP Gilmore ◽

JJG Geurts ◽

N Evangelou ◽

JCJ Bot ◽

RA van Schijndel ◽

...

Keyword(s):

Spinal Cord ◽

White Matter ◽

Mr Imaging ◽

High Field ◽

Grey Matter ◽

Great Majority ◽

Proton Density ◽

Post Mortem ◽

Mr Images ◽

The Brain

Background Post-mortem studies demonstrate extensive grey matter demyelination in MS, both in the brain and in the spinal cord. However the clinical significance of these plaques is unclear, largely because they are grossly underestimated by MR imaging at conventional field strengths. Indeed post-mortem MR studies suggest the great majority of lesions in the cerebral cortex go undetected, even when performed at high field. Similar studies have not been performed using post-mortem spinal cord material. Aim To assess the sensitivity of high field post-mortem MRI for detecting grey matter lesions in the spinal cord in MS. Methods Autopsy material was obtained from 11 MS cases and 2 controls. Proton Density-weighted images of this formalin-fixed material were acquired at 4.7Tesla before the tissue was sectioned and stained for Myelin Basic Protein. Both the tissue sections and the MR images were scored for grey matter and white matter plaques, with the readers of the MR images being blinded to the histopathology results. Results Our results indicate that post-mortem imaging at 4.7Tesla is highly sensitive for cord lesions, detecting 87% of white matter lesions and 73% of grey matter lesions. The MR changes were highly specific for demyelination, with all lesions scored on MRI corresponding to areas of demyelination. Conclusion Our work suggests that spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the functional consequences of grey matter demyelination in MS.

Download Full-text