| Degeneration of long axonal tracts is the primary cause of functional loss in spinal cord injury (SCI) patients. After mechanical trauma to the cord, many of the axons that remain intact after the initial insult succumb to secondary degenerative mechanisms in the days to weeks following injury. This provides a large therapeutic window in which to prevent further loss of axons and function. The works in this thesis are aimed at elucidating therapies to preserve the integrity of the sensory axons projecting to the medulla. First, a model was developed in which sensory axon disconnection after graded spinal contusions could be studied by measuring sensory fiber loss in their target nuclei. Subsequent studies show that neither the female estrus cycle nor preconditioning peripheral nerve injuries affected outcome. The next study shows that local infusions of a neurotrophic factor (NT-3) over the site of injury were without effect and unexpectedly, infusions aimed at the sensory fiber terminals enhanced sensory fiber degeneration. Possible reasons for this response are discussed. The final work in this thesis investigates whether pharmacological manipulation of the vasculature promotes white matter sparing and thus potentially axonal integrity. Expression of an integrin receptor (alpha6beta1) was found to increase in blood vessels during development and after injury, providing a potential target for proangiogenic therapies. However, local infusions of a small peptide agonist of alpha6beta1 above the injury site did not promote angiogenesis. Serendipitously, the control peptide (SP3) increased blood vessel diameter, possibly by affecting the activity of the alpha1beta1 integrin, with which it shares significantly homology and which is also shown to be up-regulated in blood vessels after injury. Furthermore, a correlation between vessel diameter and tissue loss was found, providing a potential target for reducing tissue loss after SCI. The model described here to assess axonal integrity provides a new tool for assessing the therapeutic potential of new drug discoveries for possible axon protective effects. The novel findings are that NT-3 can have detrimental effects, alpha1beta1 and alpha6beta1 integrins are increased in blood vessels after SCI, and that the neurons involved in autonomic dysreflexia express alpha6beta1 integrin. |
