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

Abstract

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 e ective in restoring some sensory and motor impairment in incomplete SCI patients. The long-term e ect 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 signi®cant e ect of treatment. Our data indicate that daily administration of 4-AP, over 4 weeks of treatment period, lacks any signi®cant e ect on axonal function in chronically injured rats. This could be due to (a) lack of signi®cant 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 at 30 mg/kg also did not ensure a better functional outcome.

Methylprednisolone and Interleukin-10 Reduce Gray Matter Damage in the Contused Fischer Rat Thoracic Spinal Cord but Do Not Improve Functional Outcome

“…Several reports have contested the reported long-term effects of MP on neurological recovery after SCI in the clinic (George et al, 1995;Gerndt et al, 1997;Hurlbert, 2000;Nesathurai, 1998;Short et al, 2000) and in experimental models (Faden et al, 1984;Haghighi et al, 1998;Ross et al, 1993). In agreement with these, a behavioral effect of MP could not be demonstrated in the present study.…”

“…It is clear that interference in the early inflammatory response limits the destructive secondary injury following damage to the spinal cord. Treatment with MP shortly after SCI reportedly has beneficial effects (Bracken et al, 1990(Bracken et al, , 1992, but some debate exists about its long-term effects in the clinic (George et al, 1995;Gerndt et al, 1997;Hurlbert, 2000;Nesathurai, 1998;Short et al, 2000) and in experimental models (Faden et al, 1984;Haghighi et al, 1998;Ross et al, 1993). Also, the precise mechanisms through which MP exerts its effect following SCI are poorly understood.…”

The Use of 4‐Aminopyridine (Fampridine) in Demyelinating Disorders

“…These studies (12,13,37,49,72,125) are summarized in Table 1. Some trials have shown indications of potential neurological benefit, such as enhanced motor evoked potentials (125) or reflex activity (12,13), whereas others have yielded no evident gains in function (37). These varied outcomes may be due to differences in models, e.g., acute versus chronic injury, differences in injury mechanism, species-specific differences, or other methodological issues such as drug delivery, or the sensitivity of the outcome measure.…”

Ion channel blockers and spinal cord injury

“…The data related to this area are controversial. Improved neurological status was reported in dogs with chronic SCI (Blight et al, 1991), whereas no significant effect on axonal function was reported in chronically injured rats (Haghighi et al, 1998). In addition to impairment of conduction, destruction of cell bodies and release of excitotoxins caused by K 1 are involved in the secondary damage in SCI (Liu and McAdoo, 1993), although these factors have not been studied in detail.…”