Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis

J Neuropathol Exp Neurol. 2002 Jan;61(1):23-32. doi: 10.1093/jnen/61.1.23.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / pathology*
  • Axons / ultrastructure
  • Disease Models, Animal
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Epitopes
  • Female
  • Humans
  • Inflammation
  • Male
  • Mice
  • Mice, Inbred Strains
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology*
  • Multiple Sclerosis / physiopathology
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Multiple Sclerosis, Relapsing-Remitting / pathology*
  • Multiple Sclerosis, Relapsing-Remitting / physiopathology
  • Myelin Proteolipid Protein / immunology
  • Peptide Fragments / immunology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology*
  • Statistics as Topic

Substances

  • Epitopes
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • myelin proteolipid protein (139-151)