|Budget Amount *help
¥4,000,000 (Direct Cost : ¥4,000,000)
Fiscal Year 1990 : ¥4,000,000 (Direct Cost : ¥4,000,000)
1) We investigated the effect of digitalis (cardiac glycosides) on conduction in demyelinated nerve fibers. Digitalis, a blocker of the electrogenic Na/K pump, has been shown to prevent hyperpolarization of the axonal membrane and our preliminary evidence suggested that digitalis overcomes the failure to transmit high-frequency impulses (rate-dependent block) due to hyperpolarization. Our data also suggested that digitalis partially reverses complete conduction blocks due to demyelination possibly by lowering the resting membrane potential. We performed a single fiber study in demyelinated rat ventral root fibers and a serial SEP study in rats with spinal cord demyelination after administration of digitalis, correlating with clinical signs.
2) Many patients with MS have clinically silent plaques, and clinical recovery in MS is often too rapid to be caused by remyelination. Demyelinated fibers in MS seen to transmit impulses, which could be biologically-useful after recovery of symptoms.
Based on our previous study (Kaji, Suzumura, Sumner, Brain (1988) 111 ; 675-694, Appendix 1) , which showed failure of CNS demyelinated fibers to transmit trains of impulses of as low as 50 Hz frequency (rate-dependent block) at the onset of symptoms and clinical recovery with persistent rate-dependent block, we put forward the following hypothesis on the physiological mechanism of remissions and relapses of symptoms in MS :
Clinical symptoms in MS could be caused by rate-dependent block in the absence of complete conduction block because information is coded as frequencies of impulses utilizing high-frequency range (up to 250 Hz or more) in CNS fibers (frequency modulation). Clinical recovery is attained by adaptive processes of axon terminals and postsynaptic neurons leading to re-interpretation of the modified trains of impulses. Relapses of symptoms are brought about by slight extension of the plaque or any other factors that again lower the safety factor of transmission and in turn reduce the maximal frequency that demyelinated fibers can follow, rendering the information carried in the discharge pattern uninterpretable by the post-synaptic neuron.
To test this hypothesis, we have established a model in which we can analyze coding of information in the dorsal column fibers and neurons in the gracile neuclei after vibratory stimulation on the foot pad in rats with spinal cord demyelination. Our preliminary study showed loss of information on the vibratory frequency caused by rate-dependent blocks due to demyelination (Kaji R, Kimura J, et al. Submitted to Brain). We clarified the mechanism of the recovery process by recording from demyelinated fibers (dorsal column) and postsynaptic neurons (gracile neurons) as well as ultrastructural andHRP studies in the gracile nucleus. We also examined the effect of digitalis on the impaired neural coding in this model, specifically its ability to reverses rate-dependent block.
3) Based on the above animal experiments, we examined the effect of intravenous digoxin on clinical symptoms and evoked potential parameters in patients with multiple sclerosis. Digoxin, a digitalis derivative, could successfully reverse the clinical disabilities and conduction abnormalities in those patients, albeit transiently (Kaji et al. Ann Neurol 1990 ; 28 ; 582-584). Less