Long-term effects of methylprednisolone following transection of adult rat spinal cord.
Clinically, high-dose treatment with the glucocorticosteroid, methylprednisolone (MP), within 8 h after spinal cord injury, has been shown to improve neurological recovery. The current standard of care is to administer MP as a bolus of 30 mg/kg followed by a 23-h infusion of 5.4 mg/kg/h to spinal cord injured patients. To better understand the role of MP in neuroprotection, we have studied how MP administration affects macrophage accumulation, tissue loss, and axonal dieback at 1, 2, 4 and 8 weeks after a complete transection of the eighth thoracic spinal cord in the adult rat. A 30 mg/kg dose of MP was administered intravenously at 5 min, and 2 and 4 h after injury. The number of ED1 (antibody against microglia/macrophages) -positive cells was quantified in a 500-micrometer-wide strip of tissue directly adjacent and parallel to the transection. At all time points, MP treatment led to a significant decrease in the number of ED1-positive cells in both rostral and caudal stumps. Over the 2-month post-transection period, the average MP-induced reduction in the number of ED1-positive cells was 82% in the rostral cord stump and 66% in the caudal stump. Using a computerized image analysis system, it was observed that MP treatment resulted in a significant reduction in tissue loss in both cord stumps at 2, 4 and 8 week post-injury. Over the 2-month post-lesion period, the average MP-induced reduction in tissue loss in the caudal cord stump was higher than that in the rostral stump; 48 versus 37%, respectively. Immunostaining for neurofilaments and growth-associated protein-43 (GAP-43) revealed the presence of numerous axons near and in the lesion site. Anterograde neuronal tracing with biotinylated dextran amine showed that, in MP-treated animals, dieback of vestibulospinal fibres, but not of corticospinal fibres, was significantly diminished at all time points studied. In addition, with MP administration, 1 and 2 weeks after injury, an increase in the number of vestibulospinal fibres was found at 1 and 2 mm from the transection, suggesting transient regenerative sprouting of these fibres. The results demonstrate that treatment with MP shortly after spinal cord transection in the adult rat led to a long-term reduction of ED1-positive cells and spinal tissue loss, reduced dieback of vestibulospinal fibres, and a transient sprouting of vestibulospinal fibres near the lesion at 1 and 2 weeks post-lesion. The possible relationships between the inflammatory changes, spinal tissue sparing, and axonal survival and sprouting are complex and need to be further explored.
Oudega
M
M
The Chambers Family Electron Microscopy Laboratory, The Miami Project to Cure Paralysis, University of Miami School of Medicine, Florida, USA. moudega@miamiproj.med.miami.edu
Vargas
C G
CG
Weber
A B
AB
Kleitman
N
N
Bunge
M B
MB
D000818:Animals; D002452:Cell Count / Q000187:drug effects; D005260:Female; D008264:Macrophages / Q000473:pathology; D008775:Methylprednisolone / Q000494:pharmacology*; D009000:Monocytes / Q000473:pathology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011712:Pyramidal Tracts / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D011916:Rats, Inbred F344; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D014726:Vestibular Nuclei / Q000187:drug effects / Q000503:physiopathology; D014950:Wounds, Penetrating / Q000473:pathology / Q000503:physiopathology*
D018696:Neuroprotective Agents; D008775:Methylprednisolone