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Minocycline as a neuroprotective agent following spinal cord injury Stirling, David Paul
Abstract
The mechanical impact of a spinal cord injury (SCI) triggers a cascade of secondary damage that progressively destroys an increasing amount of tissue adjacent to the primary lesion over a period of hours to weeks. The pathophysiological changes lead to necrotic, as well as apoptotic death, inflammation, demyelination, and axonal damage. In their wake, a fluid-filled cavity often forms leaving a small rim of spared white matter. While the initial mechanically destructive events cannot be reversed, the cellular inflammatory reactions occur over several hours to weeks, a timeframe during which therapeutic intervention may be achieved. This thesis examines the efficacy of minocycline, a 2nd generation tetracycline-derivative, in attenuating secondary degeneration after SCI. The results of the first series of experiments indicate that the peak of apoptosis within the ascending sensory tracts (AST) following dorsal column transection in rats occurs at one to two weeks after injury. Numerous apoptotic profiles are located within both the proximal and distal segments of the AST after injury. Although oligodendrocytes undergo apoptosis as well as microglia, the latter are the main cell type to undergo apoptosis in this model. Importantly, minocycline administration delayed up to 30 minutes after injury, significantly reduces apoptosis, prevents corticospinal tract axonal dieback, diminishes lesion size and promotes functional recovery following a dorsal column transection. The results from the second series of experiments show that minocycline treatment reduces levels of mRNA and activation of p38 mitogen-activated protein kinase (MAPK) after SCI. In addition, p38 MAPK increases early after SCI and colocalizes with neutrophils, and microglia/macrophages. The final series of experiments assessed the efficacy of minocycline or the p38 MAPK inhibitor SB203580 in promoting neurological recovery utilizing a contusion model of SCI in rats to more closely mimic the injury seen in humans. The results from these experiments indicate that delayed minocycline treatment (1 hour after injury) administered intravenously promotes tissue preservation and functional recovery after SCI. Collectively, these findings suggest that several aspects of the secondary degeneration that occurs after SCI can be prevented by minocycline application, and supports its use as a potential neuroprotective treatment following human SCI.
Item Metadata
Title |
Minocycline as a neuroprotective agent following spinal cord injury
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2005
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Description |
The mechanical impact of a spinal cord injury (SCI) triggers a cascade of secondary
damage that progressively destroys an increasing amount of tissue adjacent to the primary lesion
over a period of hours to weeks. The pathophysiological changes lead to necrotic, as well as
apoptotic death, inflammation, demyelination, and axonal damage. In their wake, a fluid-filled
cavity often forms leaving a small rim of spared white matter. While the initial mechanically
destructive events cannot be reversed, the cellular inflammatory reactions occur over several
hours to weeks, a timeframe during which therapeutic intervention may be achieved. This thesis
examines the efficacy of minocycline, a 2nd generation tetracycline-derivative, in attenuating
secondary degeneration after SCI.
The results of the first series of experiments indicate that the peak of apoptosis within the
ascending sensory tracts (AST) following dorsal column transection in rats occurs at one to two
weeks after injury. Numerous apoptotic profiles are located within both the proximal and distal
segments of the AST after injury. Although oligodendrocytes undergo apoptosis as well as
microglia, the latter are the main cell type to undergo apoptosis in this model. Importantly,
minocycline administration delayed up to 30 minutes after injury, significantly reduces
apoptosis, prevents corticospinal tract axonal dieback, diminishes lesion size and promotes
functional recovery following a dorsal column transection.
The results from the second series of experiments show that minocycline treatment
reduces levels of mRNA and activation of p38 mitogen-activated protein kinase (MAPK) after
SCI. In addition, p38 MAPK increases early after SCI and colocalizes with neutrophils, and
microglia/macrophages. The final series of experiments assessed the efficacy of minocycline or
the p38 MAPK inhibitor SB203580 in promoting neurological recovery utilizing a contusion
model of SCI in rats to more closely mimic the injury seen in humans. The results from these experiments indicate that delayed minocycline treatment (1 hour after injury) administered
intravenously promotes tissue preservation and functional recovery after SCI. Collectively, these
findings suggest that several aspects of the secondary degeneration that occurs after SCI can be
prevented by minocycline application, and supports its use as a potential neuroprotective
treatment following human SCI.
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Genre | |
Type | |
Language |
eng
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Date Available |
2009-12-22
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0092356
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2005-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.