The overall goal of this project is to advance understanding of the roles and interrelationships of inflammatory responses, demyelination, and axonal conduction block in the loss of function that follows traumatic injury to the spinal cord. This goal is directly relevant to the profound medical problems of treating acute and chronic spinal cord injury. A recent clinical trial has shown limited, but significant improvement in neurological outcome from spinal trauma, using very high doses of methylprednisolone within 8 hours of injury. However, it is still uncertain how this drug achieves its benefit, and it is difficult to identify and develop other effective treatments while the mechanisms of secondary pathological damage remain poorly understood. The present experiments will concentrate on the possible role of inflammatory responses in such secondary pathology. Pairwise-randomized, blinded experiments will be performed to examine the effects of intraperitoneal injections of silica dust (a macrophage toxin) on inflammatory responses and on functional and histological outcome from focal trauma. Injuries of the lower thoracic spinal cord will be produced in anesthetized adult guinea pigs, using a technique of compression that results in injuries of moderate severity. The outcome from injury will be monitored with behavioral tests, daily during the first week and weekly thereafter for up to three months. Animals will then be fixed for histological examination of the spinal cord in plastic sections (1 micromole) stained with toluidine blue. Quantitative morphometric sampling of myelinated axons and microvasculature will be performed in sections from the center of the lesion and from surrounding areas of the cord that experience axonal degeneration but little direct mechanical damage. Measures of functional change will be related to the quantitative morphometry of myelinated axons and vasculature in the chronic lesion and compared between experimental and control groups. Effects of silica injections on the inflammatory response will be examined in separate experiments in which the animals will be fixed for histology at 1, 2, 4, 8, or 14 days after injury. Effects of silica injections on the development of the inflammatory response will be related to the timing of effects on the secondary loss of behavioral and electrophysiological function, and to changes in circulating leukocytes. Similar techniques of injury and quantitative analysis will than be used to examine whether neurological outcome in the guinea pig model is improved by methylprednisolone (30 mg/kg i.v. bolus beginning at 45 minutes post injury) and whether any improvement is related to a particular histological change or a particular time in the evolution of secondary pathological events in the spinal cord, particularly that associated with the peak of phagocytic activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021122-09
Application #
2264062
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1987-09-01
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1996-07-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Surgery
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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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