Long-term effects of methylprednisolone following transection of adult ratspinal cord

Clinically, high-dose treatment with the glucocorticosteroid, methylprednis olone (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 co rd injured patients. To better understand the role of MP in neuroprotection , we have studied how MP administration affects macrophage accumulation, ti ssue loss, and axonal dieback at 1, 2, 4 and 8 weeks after a complete trans ection 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-mu m-wide strip of tissue directly adjacent and pa rallel to the transection. At all time points, MP treatment led to a signif icant decrease in the number of ED1-positive cells in both rostral and caud al 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 syst em, it was observed that MP treatment resulted in a significant reduction i n 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 ver sus 37%, respectively. Immunostaining for neurofilaments and growth-associa ted protein-43 (GAP-43) revealed the presence of numerous axons near and in the lesion site. Anterograde neuronal tracing with biotinylated dextran am ine showed that, in MP-treated animals, dieback of vestibulospinal fibres, but not of corticospinal fibres, was significantly diminished at all time p oints studied. In addition, with MP administration, 1 and 2 weeks after inj ury, 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 ED 1-positive cells and spinal tissue loss, reduced dieback of vestibulospinal fibres, and a transient sprouting of vestibulospinal fibres near the lesio n at 1 and 2 weeks post-lesion. The possible relationships between the infl ammatory changes, spinal tissue sparing, and axonal survival and sprouting are complex and need to be further explored.