This proposal describes a set of experiments intended to develop and investigate novel therapeutic treatments to intervene in the glutamate- mediate cellular toxicity signal that occurs during acute spinal cord injury (SCI). Acute traumatic SCI initiates a series of cellular and molecular events that include the primary physical trauma and secondary molecular injury cascades. The secondary pathways result in potentially preventable continued neuronal cell death due to glutamate-mediated excitotoxicity, free radical damage, cytokines inflammation, lipid peroxidation, necrosis, and apoptosis. Pharmacological NMDA antagonists have recently been shown to provide beneficial neuroprotection by reducing glutamate-mediated excitotoxicity in rat SCI models and have two negative characteristics that limit their clinical utility as treatments for acute SCI. First, their high toxicity causes many metabolic and neurologic adverse side effects. Second, the rapid induction of glutamate levels after an acute injury to the CNS makes blocking the initial stages of the signaling pathway logistically difficult in the clinical setting. The premise of the following proposal is to design new methods of intervening in the glutamate toxicity signal utilizing a rat SCI model that fully addresses these two pitfalls. The first issue of safety will be addressed by testing an immunologic means of inhibiting NMDA receptors. Thereafter, the issue of logistics will be dealt with by identifying and blocking downstream targets of NMDA activation utilizing novel transcription factor decoys.
