Effect of 4-aminopyridine and single-dose methylprednisolone on functional recovery after a chronic spinal cord injury

The demyelination process is an important factor contributing to long term sensory and motor impairments after spinal cord injury (SCI), Exposure of axonal K+ channels after demyelination may contribute to blockage of action potentials across the injury site. A K+ channel blocker, 4-aminopyridine (4-AP), has been effective in restoring some sensory and motor impairment in incomplete SCI patients. The long-term effect of this compound in chronic model of SCI is not known. In this study. after a compression injury of 50 grams in rats, a randomized treatment was initiated 3 weeks after the initial injury which was followed by daily administration of 4-AP at 2 mg/kg (n = 8), 4 mg/kg (n = 8), and 6 mg/kg (n = 8) for 4 weeks. A group of methylprednisolone (MP)-treated (30 mg/kg, n = 8) and non-treated animals (n = 8) were included for comparison. The functional motor outcome was measured in each animal at regular time points up to 4 weeks post-treatment. All animals receiving 6 mg/kg developed generalized seizure and were excluded from the study, In the other animal groups, analysis of the behavioral outcome and neuro-pathological changes were essentially similar and did not show any significant effect of treatment. Our data indicate that daily administration of 4-AP, over 4 weeks of treatment period, lacks any significant effect on axonal function in chronically injured rats, This could be due to (a) lack of significant numbers of demyelinated axons which could improve the functional outcome and (b) a treatment regimen that was not adequate to contribute to a better functional outcome. One time bolus-administration of MP al 30 mg/kg also did not ensure a better functional outcome.