This is a re-revised application to PA-03-165, """"""""Neuroprotective CMS Barriers in Neurological Diseases"""""""". The blood-spinal cord-barrier (BSCB) consists of a network of specialized endothelial cells that selectively restrict the transport of blood and plasma components into the cellular microenvironment of the spinal cord. Traumatic spinal cord injury (SCI) ruptures spinal blood vessels, opening the BSCB and introduces blood-born substances into the spinal cord that contribute to inflammatory-mediated secondary tissue loss. The objectives of this project are to characterize the molecular responses of spinal cord blood vessels to traumatic injury, focusing on the injury-induced loss of vascular integrity via increase in serum protein leakage as well as through the loss of tight- and adherens junction proteins; the molecular elements that comprise the BSCB. We have determined that the class of drugs known as phosphodiesterase-inhibitors (PDE-ls) dramatically reduce the loss of BSCB integrity following spinal contusion injury. We propose to determine whether acute treatment with 2 PDE-ls, a specific PDE4a-inhibitor called rolipram and a non- selective PDE-I known as pentoxifylline reduce protein extravasation following SCI; protecting the BSCB and promoting improved neurological outcome. As methylprednisalone is currently the only drug used to treat SCI in the clinic, the potential use of a class of drugs that improve vascular integrity should be explored. We will assess BSCB status through a longitudinal study employing non-invasive Dynamic Contrast-Enhanced- Magnetic Resonance Imaging (DCE-MRI), allowing us to follow BSCB and behavioral outcomes within the same set of animals over time. In addition, the goals of this specific PA focus on the state of barrier properties in neurological states. We have preliminary data that indicates a progressive spatial and temporal loss of BSCB function in the chronic period of spinal cord injury (8 months). As the previous spinal cord injury literature suggests that BSCB function is restored by 1 month post-injury, we believe these preliminary results are extremely important as they suggest a state of ongoing barrier loss and dysfunction. We propose to explore the nature of this chronic BSCB dysfunction over a time course of 1 year. In addition, we will also explore whether treatment with PDE-ls in the acute phase results in a repaired BSCB in the chronic. ? ? ?
