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

• Published in: Experimental neurology Vol. 197; no. 2; pp. 373 - 385
• Main Authors: Papadopoulos, Dimitrios, Pham-Dinh, Danielle, Reynolds, Richard
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.02.2006; Elsevier
• Subjects: Animals; Atrophy; Axonal loss; Axons - metabolism; Axons - pathology; Biological and medical sciences; CD11b Antigen - metabolism; Demyelination; Disease Models, Animal; EAE; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - physiopathology; Female; Injuries of the nervous system and the skull. Diseases due to physical agents; Medical sciences; MOG; Multiple sclerosis; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Multiple Sclerosis, Relapsing-Remitting - pathology; Multiple Sclerosis, Relapsing-Remitting - physiopathology; Myelin Proteins; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Myelitis - etiology; Myelitis - pathology; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Neurology; Rats; Remyelination; Spinal Cord - pathology; Spinal cord atrophy; Statistics as Topic; Time Factors; Traumas. Diseases due to physical agents; Multiple sclerosis; MOG; Demyelination; EAE; Spinal cord atrophy; Axonal loss; Remyelination; Autoimmunity; Immunohistochemistry; Spinal cord; Relapse; Rat; Pathogenesis; Central nervous system; Ox; Inflammatory disease; Atrophy; Disability; Irreversible; Neurological disorder; Ungulata; Evaluation; Nervous system diseases; Mimic; Myelin; Rodentia; Axon; Inflammation; Section; Vertebrata; Anatomic pathology; Chronic; Mammalia; Onset time; Treatment; Mouse; Animal; Central nervous system disease; Severity score; Models; Artiodactyla; Macrophage
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2005.10.033

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.