Minocycline as a neuroprotective agent following spinal cord injury.

摘要

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.