Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat

Dimitrios Papadopoulos, Danielle Pham-Dinh, Richard Reynolds
Experimental Neurology 2006, 197 (2): 373-85
Axonal loss is now considered a consistent feature of MS pathology and evidence suggests that its accumulation may be the pathological correlate for the development of irreversible disability. In this study, we investigated the features of axonal loss in myelin autoimmunity and tested the hypothesis that loss of axons determines permanent neurological impairment in a model of inflammatory demyelination that closely mimics the pathology and course of MS. EAE was induced in DA rats by injection of recombinant mouse MOG with IFA. Animals that developed progressive EAE were killed at several time points after disease onset and animals that followed a chronic relapsing-remitting course of EAE were killed at approximately 4 months, exhibiting varying degrees of residual disability. Toluidine blue staining of semithin sections and immunohistochemistry for OX-42 were used to quantify demyelination, remyelination, inflammation and axonal loss in the spinal cord of MOG-EAE rats. In progressive EAE, the degree of axon loss, demyelination and inflammation all correlated significantly with clinical severity scores and a causative role for macrophages in the pathogenesis of axonal injury is suggested. However, in the chronic stage of relapsing-remitting EAE, in rats having suffered a variable number of relapses, only axonal loss correlated significantly with clinical severity scores. In addition, both axonal loss and clinical severity scores correlated with the number of relapses. These findings imply that secondary, or 'bystander', axonal loss is the main determinant of irreversible neurological disability in MOG-EAE and make the model a useful tool for the investigation of mechanisms of axonal loss and the evaluation of the benefits of neuroprotective therapies under conditions of antibody-mediated inflammatory demyelination.

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