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The Journal of Neuroscience, March 3, 2004, 24(9):2182-2190; doi:10.1523/JNEUROSCI.5275-03.2004
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Development/Plasticity/Repair
Minocycline Treatment Reduces Delayed Oligodendrocyte Death, Attenuates Axonal Dieback, and Improves Functional Outcome after Spinal Cord Injury
David P. Stirling, Kourosh Khodarahmi, Jie Liu, Lowell T. McPhail, Christopher B. McBride, John D. Steeves, Matt S. Ramer, andWolfram Tetzlaff International Collaboration On Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4
Minocycline has been demonstrated to be neuroprotective after spinal cord injury (SCI). However, the cellular consequences of minocycline treatment on the secondary injury response are poorly understood. We examined the ability of minocycline to reduce oligodendrocyte apoptosis, microglial/macrophage activation, corticospinal tract (CST) dieback, and lesion size and to improve functional outcome after SCI. Adult rats were subjected to a C7-C8 dorsal column transection, and the presence of apoptotic oligodendrocytes was assessed within the ascending sensory tract (AST) and descending CST in segments (3-7 mm) both proximal and distal to the injury site. Surprisingly, the numbers of dying oligodendrocytes in the proximal and distal segments were comparable, suggesting more than the lack of axon-cell body contiguity played a role in their demise. Minocycline or vehicle control was injected into the intraperitoneal cavity 30 min and 8 hr after SCI and thereafter twice daily for 2 d. We report a reduction of apoptotic oligodendrocytes and microglia within both proximal and distal segments of the AST after minocycline treatment, using immunostaining for active caspase-3 and Hoechst 33258 staining in combination with cell-specific markers. Activated microglial/macrophage density was reduced remote to the lesion as well as at the lesion site. Both CST dieback and lesion size were diminished after minocycline treatment. Footprint analysis revealed improved functional outcome after minocycline treatment. Thus, minocycline ameliorates multiple secondary events after SCI, rendering this clinically used drug an attractive candidate for SCI treatment trials.
Key words: oligodendrocyte; apoptosis; spinal cord injury; caspase-3; minocycline; microglia; macrophages; neuroprotection; axonal dieback; footprint analysis
Received Nov 29, 2003; revised January 6, 2004; accepted January 6, 2004.
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