Mechanisms of neurological dysfunction and recovery in acute experimental allergic encephalomyelitis in the lewis rat

Abstract

The submitted material comprises 9 papers investigating the mechanisms of neurological dysfunction and recovery in Lewis rats with acute experimental allergic encephalomyelitis (EAE) induced by inoculation with whole spinal cord or myelin basic protein (MBP). EAE is widely studied as an animal model of multiple sclerosis (MS), a human central nervous system (CNS) demyelinating disease of unknown aetiology. Many immunotherapeutic strategies have been found to be successful in suppressing or improving the neurological signs of EAE, and this has led to the application of these therapies to the management of MS. Surprisingly, however, the mechanisms producing the neurological signs of EAE in the most widely studied animals, the small rodents, are unknown because the pathophysiology of EAE has been severely neglected. The present work was undertaken to investigate the pathophysiology of acute EAE in the Lewis rat.On the basis of the findings of combined histological and electrophysiological studies, the hypothesis is developed that demyelination-induced nerve conduction block in specific regions of the peripheral nervous system (PNS) and the CNS accounts for the neurological signs of whole spinal cord-induced and MBP-induced acute EAE in the Lewis rat. The dorsal and ventral spinal roots and the CNS parts of the dorsal root entry and ventral root exit zones of the spinal cord were sites of predilection for demyelination. In addition the sacrococcygeal dorsal root ganglia showed prominent demyelination in whole spinal cord-induced EAE. Demyelination affected fibres of all calibres, and the neurological dysfunction reflected conduction block in myelinated fibres of both large and small diameter. From studies on the recovery process it was concluded that the rapid clinical recovery from acute EAE in Lewis rats is due to the restoration of nerve conduction in the PNS and CNS as the result of rapid repair by Schwann cells and oligodendrocytes respectively. These findings shed new light on the possible mechanisms whereby inflammatory demyelinating diseases such as MS may interfere with the,function of the nervous system and how spontaneous recovery may occur. These results also emphasize a previously underestimated difference between MS and whole spinal cord-induced or MBP-induced EAE. This difference should be considered whenever EAE is studied as a model of MS.