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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‐μm‐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.