The overall goal of this project is a deeper understanding of the role of demyelination in loss of function following traumatic injury to the spinal cored. Its medial significance lies in the importance of knowing the mechanisms of injury and recovery as a first step in developing therapy for this devastating currently untreatment condition. Such therapy might involve improvement of remyelination or pharmacological reversal of action potential conduction failure. The study will also continue to provide basic information on the biophysical organization of myelinated axon, and on the more general phenomenon of demyelination pathophysiology in the mammalian nervous system. A new model of spinal cord compression injury in adult guinea pigs will be quantified, morphometrically, electrophysiologically and functionally. This preparation has been developed as a result of experience with cat spinal cord weight-drop contusion injury, and it provides substantial advantages for studying chronic injuries, particularly for in vitro electrophysiology. It also demonstrates a unique advantage in that there is a clear separation, at the level of behavioral function, between acute and delayed damage to the spinal cord. It will be used specifically to examine differences in myelinated axon structure and physiology between animals which recover function and those which do not, following similar primary injuries. The effect of lesion length on remyelination and chronic conduction deficits will also be investigated. This is an essential but neglected issue in modeling clinical trauma, where lesions are typically extensive. Intracellular recordings will be made from axons in spinal cord tracts isolated from animals at a succession of stages after experimental spinal cord injury. The quantitative morphometry of the lesion will be examined in 1 micron plastic sections, using line sampling techniques. A particular concern will be to identify structural and physiological differences between axons that respond and those that do not respond to the application of 4-aminopyridine (4-AP), a potassium channel blocker that has been shown, during the first grant period, to restore conduction in some axons of chronically injured cords. Intracellular injection of horseradish peroxidase (HRP) will be used to allow correlation of structure and function in individual fibers. The conduction characteristics of axons, their temperature of conduction block, and their responses to extracellular application of 4-AP, will be measured prior to injection of HRP. Subsequently, these axons will be identified in vibratome sections and embedded in plastic for morphometric studies using semi-thin and thin sections.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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Purdue University
Schools of Veterinary Medicine
West Lafayette
United States
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Yates, Jennifer R; Heyes, Melvyn P; Blight, Andrew R (2006) 4-chloro-3-hydroxyanthranilate reduces local quinolinic acid synthesis, improves functional recovery, and preserves white matter after spinal cord injury. J Neurotrauma 23:866-81
Jaeger, C B; Blight, A R (1997) Spinal cord compression injury in guinea pigs: structural changes of endothelium and its perivascular cell associations after blood-brain barrier breakdown and repair. Exp Neurol 144:381-99
Blight, A R; Leroy Jr, E C; Heyes, M P (1997) Quinolinic acid accumulation in injured spinal cord: time course, distribution, and species differences between rat and guinea pig. J Neurotrauma 14:89-98
Gruner, J A; Yee, A K; Blight, A R (1996) Histological and functional evaluation of experimental spinal cord injury: evidence of a stepwise response to graded compression. Brain Res 729:90-101
Cohen, T I; Weinberg, R J; Blight, A R (1996) Intrathecal infusion of the nitric oxide synthase inhibitor N-methyl L-arginine after experimental spinal cord injury in guinea pigs. J Neurotrauma 13:361-9
Blight, A R; Cohen, T I; Saito, K et al. (1995) Quinolinic acid accumulation and functional deficits following experimental spinal cord injury. Brain 118 ( Pt 3):735-52
Blight, A R (1994) Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage. Neuroscience 60:263-73
Blight, A R (1993) Remyelination, revascularization, and recovery of function in experimental spinal cord injury. Adv Neurol 59:91-104
Blight, A R; Saito, K; Heyes, M P (1993) Increased levels of the excitotoxin quinolinic acid in spinal cord following contusion injury. Brain Res 632:314-6
Blight, A R (1992) Macrophages and inflammatory damage in spinal cord injury. J Neurotrauma 9 Suppl 1:S83-91

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