Fabes, J.; (2006) Investigating the role of ephrin signalling in spinal cord injury. Doctoral thesis , University of London.

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Abstract

Spinal cord injury in adult mammals commonly leads to the permanent loss of motor and sensory function in regions of the body below the level of injury. The inability of the central nervous system to regenerate is, in part, due to the presence of growth-inhibitory agents surrounding the lesion site. This thesis presents a previously unreported, inhibitory interaction between ephrinB2 expressed on reactive astrocytes and the EphA4 receptor present on lesioned corticospinal tract axons. This interaction appears to mediate the unusually large retraction of the corticospinal tract away from spinal cord injury sites. An attempt to interfere with this interaction by implanting a cell line secreting the ephrinA5 receptor binding domain is reported. While this approach induced improvements in regenerative sprouting from the corticospinal tract, complications with immune rejection and cell proliferation stopped further investigation. A second intervention using a small peptide with high affinity and specificity for the EphA4 receptor is also reported. Intrathecal infusion of this peptide for 14 or 28 days after injury reversed the retraction of the corticospinal tract and induced improvements in regenerative sprouting from corticospinal and rubrospinal tracts following dorsal or lateral white matter transection injuries. Sprouts were seen to migrate long distances, often to the astrocyte margin of the lesion cavity. Astrocyte behaviour following injury was also altered with the formation of astrocytic 'bridges' into the lesion cavity along which regenerating axons grew. Functional recovery was also enhanced with improvements in the paw reaching assay within 10 days of a unilateral dorsal column lesion with a 30% recovery of function at 28 days post-operation. The simplicity of this intervention and direct translation to human application make it a promising candidate for use in combinatorial approaches to human spinal cord injury treatment.

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