Dose responses of three 4-aminopyridine derivatives on axonal conduction in spinal cord trauma

To explore novel treatments for enhancing conduction through traumatically injured spinal cord we have synthesized structurally distinct pyridine based compounds; N-(4-pyridyl) methyl carbamate, N-(4-pyridyl) ethyl carbamate, and N-(4-pyridyl) t-butyl carbamate. With the use of a double sucrose gap-recording chamber we perform a dose-response assay to examine the effects of these compounds on axonal conduction following an in vitro stretch injury. The tested compounds significantly enhanced axonal conduction to the stretch injured cord at 1 mu M, a dose that coincides with the clinically relevant dose of potassium channel blocker 4-aminopyridine (4-AP). Methyl carbamate enhanced conduction maximally at 100 mu M. This is also the most effective concentration of 4-AP in vitro. The other compounds ethyl carbamate and t-butyl carbamate enhanced conduction maximally at lower concentrations of 10 and 1 mu M. At higher concentrations each of these compounds continued to increased CAP amplitude, however not significantly. Additionally, two of the compounds ethyl and t-butyl carbamate appear to have negative effects on CAP amplitude when administered at or beyond 100 mu M. These compounds demonstrate the possibility that derivatives of 4-AP can retain the ability to increase axonal conduction in the injured spinal cord. (C) 2005 Elsevier B.V. All rights reserved.