Adequate neurotrophic support is essential for spinal cord regeneration; however, production of neurotrophins and neurotrophic cytokines at the site of spinal cord injury (SCI) is insufficient. The blood-brain/blood-spinal cord barrier (BBB/BSCB) mediates permeation of selective neurotrophic cytokines from the periphery. We propose that the transport system for leukemia inhibitory factor (LIF) at the BSCB is upregulated after SCI, and that enhanced transport of LIF benefits functional recovery. To test the hypothesis that LIF crosses the BSCB by receptor-related transport and that the transport system is upregulated after SCI, we will measure blood-to-spinal cord transfer of 12SI-LIF, test the effects of different classes of transport inhibitors, and compare the results with that of epidermal growth factor (125I-EGF). We expect that 12SI-LIF entry will be decreased by a LIF receptor antibody whereas 12SI-EGF entry will be decreased by polycationic peptides and dansylcadaverin but not by an EGF receptor antibody. This will support the concept that LIF crosses the BSCB by receptor-mediated transport while EGF does so by adsorptive endocytosis. We will further determine spinal cord uptake of 125I-LIF and 1251-EGF in various regions and time course after injury, compare the results with those of permeability markers (radioactively labeled albumin and inulin as indicators of barrier disruption), and test the effects of receptor antibodies and endocytosis inhibitors on the increased radiotracer uptake after SCI. We expect that SCI upregulates receptor-related transport (for LIF) without affecting adsorptive transcytosis (for EGF), and that enhanced LIF transport correlates with increased endothelial LIFRalpha receptor expression. To test the hypothesis that LIF benefits spinal cord regeneration after crossing the BSCB, we will determine histological and electrophysiological evidence of axonal regeneration. We expect that tract tracing, neurofilament staining, and intraspinal conduction of evoked potentials will be increased by LIF treatment after peripheral delivery when its transport is upregulated. These changes will coincide with improved behavioral performance. To test the hypothesis that methylprednisolone potentiates the therapeutic effects of LIF and upregulates LIF transport, we will examine not only these regeneration parameters but also transport efficacy after methylprednisolone or combined treatment. By completing these studies, we will have demonstrated that transport of neurotrophic cytokines after SCI can be modulated to facilitate functional restoration. Therefore, the BBB/BSCB is not a simple barrier but also a gate for spinal cord regeneration. Understanding the mechanisms of cytokine transport at this regulatory interface would help in the design of new approaches to treat SCI.
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