Enhanced axonal conduction following application of pyridine based compounds to the mechanically injured spinal cord

The present study investigates the effects of pyridine based potassium channel blockers on axonal conduction following mechanical spinal cord injury. Conduction block through the injured spinal cord manifests in part from increased activity of voltage gated potassium channels. Efflux of potassium ions from these otherwise muted channels is amplified following disruption of the myelin sheath with the underlying axon. In this regard, reducing the activity of these channels with appropriate potassium channel blockers will assist in the recovery of conduction through the injured tissue. With the aid of a specialized double sucrose gap recording chamber (DSGRC), compound action potentials (CAP) from the ventral white matter (WM) of mammalian spinal cord were monitored before, during, and after application of such potassium channel blockers. Initial testing revealed that 4-aminopyridine (4-AP) increased CAP amplitude nearly 100%, albeit, with significant decreases in axonal responsiveness to dual and multiple stimuli. In an effort to maintain the channel blocking ability of 4-AP, devoid of the negative side effects associated with it both experimentally and clinically, we derived several compounds similar in structure to 4-AP. Subsequent studies using the derived pyridine based compounds indicated that they maintain the ability to increase CAP amplitude following trauma with fewer negative effects. Concurrent dose response testing indicated each compound significantly enhances and emits a biphasic response on CAP amplitude. These results are similar to the effects of 4-AP on CAP amplitude. Anatomical analysis of axonal pathology following injury confirmed the relevance of the therapeutic measures applied in this study. Focusing on stretch induced trauma to the WM, samples obtained at two different time points revealed that the continuity of the myelin sheath with the underlying axon is severely disrupted. In addition, the number of axons with larger diameters is significantly reduced after injury. The pathology observed in this study is consistent with that reported following other models of spinal cord induced trauma. These results indicate that axons exposed to mechanical trauma undergo significant disruption that has horrific effects on axonal conduction. The results of which can be ameliorated through pharmacological intervention aimed at enhancing function