Evaluation of a Novel Model of Blast-Induced Traumatic Brain Injury

Traumatic brain injury (TBI) has consistently accounted for a significant proportion of the casualties of modern war, and blast-related neurotrauma is associated with the severest casualties of current military operations in the Middle East (Armonda, et al., 2006). This research proposal will evaluate the utility of the drug diazoxide (DZ), in reducing the long-term effects of blast induced TBI. DZ, a mitochondrial ATP- sensitive potassium (KATP) channel opener, has exhibited remarkable neuroprotective properties in a wide range of TBI, stroke, and spinal cord injury models. DZ has a combination of effects, including protection of endothelial cells and blood-brain barrier function (Lenzser, Kis, Bari, & Busija, 2005), reduced neuron excitability (Griesemer, Zawar, & Neumcke, 2002), decreased extracellular glutamate and NMDA receptor activity (Pamenter, Shin, Cooray, & Buck, 2008), enhanced uptake of glutamate by astrocyte glutamate transporters (Sun, et al., 2008), reduced mitochondrial transition activity in injured cells (Wu, et al., 2006), reduced neuroinflammation (Liu, et al., 2006), induction of heat shock proteins (Blondeau, Plamondon, Richelme, Heurteaux, & Lazdunski, 2000), and oxidative stress (Teshima, et al., 2003). However, investigation of the effects of DZ in a mouse animal model of blast-induced TBI is nonexistent. To undertake this research, a novel model of blast-induced TBI that employs a high intensity focused ultrasound (HIFU) blast will be used. HIFU will permit investigators to explore the relationship between blast waveform characteristics and the type and extent of CNS injury by allowing for the precise and controlled localization of the blast wave. HIFU may also serve as a practical, “bench-top” alternative to other more complex and time consuming models of TBI. This research will also address a novel approach to understanding the effects of blast exposure on neurological function. To date, little work has been performed to assess the impact of blast upon neuronal cell adhesion molecule (NCAM) expression in the brain. NCAM acts as a “connector” of neural circuits in the CNS, mediating important roles in memory and learning. Disruption of NCAM function may underlie some of the cognitive impairments seen after blast exposure. Preliminary results from our lab indicate that HIFU injury adversely affects NCAM expression.