Demyelination in spinal cord injury and multiple sclerosis: what can we do to enhance functional recovery?
Demyelination in white matter tracts has been observed in experimental and human spinal cord injury. The pathophysiology of demyelinated axons depends, in part, on their ion channel organization. Myelinated axons display a complementary distribution of sodium channels (clustered in the nodal axon membrane) and fast potassium channels (in the internodal axon membrane). The low density of sodium channels in the internodal axon membrane will impede conduction after demyelination. Moreover, "unmasked" potassium channels will tend to clamp the axon membrane close to EK, interfering with conduction in demyelinated axons. Pharmacologic blockade of these potassium channels can increase the safety factor for conduction in demyelinated axons. Restoration of conduction in demyelinated axons, so that action potentials can traverse the zone without myelin, appears to underly clinical remissions in patients with multiple sclerosis and may occur in some patients with spinal cord injury. At a cellular level, conduction through demyelinated axon regions can be facilitated by several mechanisms, including remyelination, development of excitability in demyelinated regions (which requires an adequate density of sodium channels), and impedance matching. Astrocytes have been shown to establish a specific relationship with sodium channel-rich regions of the axon membrane, and may play a role in the deployment and/or maintenance of sodium channels within the demyelinated axon membrane. Calcium influx appears to play a critical role in the cascade of events leading to secondary injury after spinal cord trauma. Recent observations suggest the hypothesis that myelin damage in spinal cord trauma may be mediated, at least in part, by influx of calcium into an intracellular compartment. As the route of calcium entry is identified and characterized, it may be possible to design strategies that will limit secondary injury after CNS trauma. The deleterious effects of calcium in injured white matter accumulate gradually, which suggests the potential reversibility of dysfunction in spinal cord tracts if treated early after trauma.
Waxman
S G
SG
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D003711:Demyelinating Diseases / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology*; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D013116:Spinal Cord / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology*