Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.

It is widely accepted that the adult mammalian central nervous system (CNS) is unable to regenerate axons. In addition to physical or molecular barriers presented by glial scarring at the lesion site, it has been suggested that the normal myelinated CNS environment contains potent growth inhibitors or lacks growth-promoting molecules. Here we investigate whether adult CNS white matter can support long-distance regeneration of adult axons in the absence of glial scarring, by using a microtransplantation technique that minimizes scarring to inject minute volumes of dissociated adult rat dorsal root ganglia directly into adult rat CNS pathways. This atraumatic injection procedure allowed considerable numbers of regenerating adult axons immediate access to the host glial terrain, where we found that they rapidly extended for long distances in white matter, eventually invading grey matter. Abortive regeneration correlated precisely with increased levels of proteoglycans within the extracellular matrix at the transplant interface, whereas successfully regenerating transplants were associated with minimal upregulation of these molecules. Our results demonstrate, to our knowledge for the first time, that reactive glial extracellular matrix at the lesion site is directly associated with failure of axon regrowth in vivo, and that adult myelinated white matter tracts beyond the glial scar can be highly permissive for regeneration.

Post-traumatic cystic cavitation, in which the size and severity of a CNS injury progress from a small area of direct trauma to a greatly enlarged secondary injury surrounded by glial scar tissue, is a poorly understood complication of damage to the brain and spinal cord. Using minimally invasive techniques to avoid primary physical injury, this study demonstrates in vivo that inflammatory processes alone initiate a cascade of secondary tissue damage, progressive cavitation, and glial scarring in the CNS. An in vitro model allowed us to test the hypothesis that specific molecules that stimulate macrophage inflammatory activation are an important step in initiating secondary neuropathology. Time-lapse video analyses of inflammationinduced cavitation in our in vitro model revealed that this process occurs primarily via a previously undescribed cellular mechanism involving dramatic astrocyte morphological changes and rapid migration. The physical process of cavitation leads to astrocyte abandonment of neuronal processes, neurite stretching, and secondary injury. The macrophage mannose receptor and the complement receptor type 3 ␤2-integrin are implicated in the cascade that induces cavity and scar formation. We also demonstrate that anti-inflammatory agents modulating transcription via the nuclear hormone receptor peroxisome proliferator-activated receptor-␥ may be therapeutic in preventing progressive cavitation by limiting inflammation and subsequent secondary damage after CNS injury. Injury to the adult mammalian C NS leads to a complex series of cellular and molecular events, as cells respond to trauma and attempt to repair damaged regions of the brain or spinal cord (for review, see Fitch and Silver, 1999a). Unlike the successf ul healing responses in the peripheral nervous system, adult C NS injury leads to permanent disability, because most severed axons fail to regenerate (Ramon y C ajal, 1928;Guth, 1975;Reier et al., 1983). A phenomenon that adds to the complexity of regenerative failure is the process of progressive cavitation in which, after days to weeks, a C NS injury can expand in size leading to a scarencapsulated cavity many times the size of the initial wound (Balentine, 1978). Although various hypotheses suggest that this secondary process of cavitation is related to ischemia (Balentine, 1978), hemorrhage (Ducker et al., 1971;Wallace et al., 1987), lysozyme activity (Kao et al., 1977), pulsatile hydrodynamics (Williams et al., 1981), or macrophage infiltration and inflammation (Blight, 1991a(Blight, , 1994Szczepanik et al., 1996;Fitch and Silver, 1997a;Z hang et al., 1997), the underlying causes of progressive axon damage and the cellular mechanisms that lead to cyst formation are poorly understood. Insights into this process will provide direction for therapeutic intervention designed to minimize secondary damage and lead to enhanced function after a debilitating injury.In this study we have used both in vivo and in vitro models to test our hypothesis that post-traumatic inflammation can lead to ...

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