Axon Loss in the Spinal Cord Determines Permanent Neurological Disability in an Animal Model of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Most patients undergo an initial relapsing-remitting (RR-MS) course that transforms into a relentless neurodegenerative disorder, termed secondary progressive (SP)-MS. Reversible inflammation and demyelination account readily for the pattern of RR-MS but provide an unsatisfactory explanation for irrevocable decline in SP-MS. Axon loss is thought to be responsible for progressive, non-remitting neurological disability during SP-MS. There is considerable potential for neuroprotective therapies in MS, but their application awaits animal models in which axonal loss correlates with permanent neurological disability. In this report, we describe quantitative immunohistochemical methods that correlate inflammation and axonal loss with neurological disability in chronic-relapsing experimental autoimmune encephalomyelitis (EAE). At first attack, CNS inflammation, but not axon loss, correlated with the degree of neurological disability. In contrast, fixed neurological impairment in chronic EAE correlated with axon loss that, in turn, correlated with the number of symptomatic attacks. As proposed for MS, these observations imply a causal relationship between inflammation, axon loss, and irreversible neurological disability. This chronic-relapsing EAE model provides an excellent platform for 2 critical objectives: investigating mechanisms of axon loss and evaluating efficacy of neuroprotective therapies.

Hyaluronan Anchored to Activated CD44 on Central Nervous System Vascular Endothelial Cells Promotes Lymphocyte Extravasation in Experimental Autoimmune Encephalomyelitis

“…Axonal degeneration is responsible for chronic disability in MS and EAE (50). We attempted to quantify neurofilament-L labeling but due to the extensive and highly variable axonal damage were unable to produce reliable counts.…”

Cell Therapy for Multiple Sclerosis

“…Moreover, remyelination is typically incomplete and ultimately fails in the setting of recurrent episodes contributing to the progressive demyelination, gliosis, axonal damage, and neurodegeneration typically noted in MS [66,67]. Several studies have indicated that axonal pathology is the best correlate of chronic neurological impairment in MS and its animal model, experimental autoimmune encephalomyelitis (EAE) [68][69][70][71][72][73].…”

“…In this model, a T cell-mediated autoimmune process causes an acute paralytic disease due to severe axonal injury and demyelination. Subsequently, the mice remain in a fixed neurological sequel, the severity of which is correlated with the extent of axonal loss [73]. NPC transplantation in MOG35-55-induced EAE mice attenuated brain inflammation, reduced acute and chronic axonal injury and demyelination, and improved the overall clinical and neurophysiological performance of the CNS of the mice [173,174].…”

Evaluation of corticospinal axon loss by fluorescent dye tracing in mice with experimental autoimmune encephalomyelitis

“…Thus, there is a high correlation between the axonal loss and the persistent neurological deficit in the chronic-relapsing EAE van Waesberghe et al, 1999). However, one problem in acute EAE models is that in many cases the structural damage is not reflected in the clinical deficit (Wujek et al, 2002). It is possible that the irreversible axonal damage occurs in the early stage of EAE, but may be limited to a small fraction of axons from a given axonal tract system, which can be compensated by the remaining intact fibers.…”