Spinal cord injury (SCI) triggers a cascade of inflammatory processes that exacerbate the mechanical insult and interfere with the recovery of spinal cord function. This secondary damage is believed to be at least in part due to the collateral loss of uninjured neurons through the activity of cytotoxic radicals produced by invading neutrophils. The selective inactivation of peroxynitrite-dependent radicals by raising levels of their natural scavenger uric acid has proven to have therapeutic value in a SCI model with uric acid-treated animals showing considerably reduced secondary spinal cord tissue damage and significantly improved functional recovery by comparison with controls. These results suggest that raising uric acid levels after SCI may provide a natural means of limiting secondary damage to the spinal cord tissues and promoting better functional recovery. To assess this possibility further, it is of primary importance to determine how long after SCI uric acid treatment remains effective and provide further evidence concerning its mode of action. This will enable us to predict whether the established natural means of raising serum uric acid levels in humans, administration of its precursor inosine, may provide the foundation for the first line treatment of SCI. The loss of function due to a spinal cord injury is considerably worsened when the body's response to the damage causes the death of nerve cells that initially survived the injury. A major contribution to this secondary loss of nerve cells comes from radicals that can be chemically inactivated by uric acid, a component of human serum. In this proposal we will use a model system to determine whether raising uric acid levels may provide a safe, natural means of preventing secondary nerve cell death and improving the outcome of spinal cord injury.
