INTRANASAL INSULIN TO INCREASE GLUCOSE UPTAKE AND IMPROVE OUTCOME AFTER MILD TO MODERATE TBI: A BENCH-TO-BEDSIDE APPROACH

Traumatic brain injury (TBI) is a serious health problem that affects approximately 1.5 million people in the United States each year and causes serious cognitive and physical deficits. TBI results in a marked reduction in glucose uptake that can last for years after injury. Intranasal insulin administration has been shown to increase cerebral glucose uptake and improve memory function in normal subjects and patients with Alzheimer’s disease, without affecting systemic blood glucose or insulin levels. Our preliminary preclinical data demonstrates that after a moderate TBI in rats, intranasal insulin administered within 4 hours after injury significantly increases glucose uptake in the hippocampus, improves cognitive function, and reduces inflammation. However, the therapeutic window of intranasal insulin and the mechanism of insulin have not been fully elucidated, and the utility of this therapy in the clinic has not been investigated. We hypothesize that intranasal insulin administration in the acute or sub-acute period after injury will reduce TBI symptoms and impairments in animals exposed to mild or moderate TBI via increasing glucose uptake and reducing inflammation. To test this hypothesis, we propose two specific aims. The first aim will demonstrate that intranasal insulin improves functional and histological outcomes in an animal model of moderate TBI. This aim will assess the therapeutic window for intranasal insulin administration and assess cognitive function, glucose uptake, and histological measures. The second aim will demonstrate that intranasal insulin improves functional and histological outcomes in an animal model of mild TBI. This aim will also assess the therapeutic window for intranasal insulin administration and assess cognitive function, glucose uptake, and histological measures after mild injury. This proposal will be the first study to explore the therapeutic window of intranasal insulin in mild and moderate TBI in rodents, utilizing a team of scientists with expertise in both preclinical and clinical models, as well as non-invasive PET imaging. This proposal will increase the understanding of the utility of intranasal insulin administration as a therapeutic approach for TBI treatment. This proposal will also provide a safe and effective treatment for TBI, which would not only improve the quality of life of service-members affected by these conditions, but also likely promote better recovery and community re-integration after injury. The preclinical work will provide essential information on mechanism and therapeutic window. Further, it is an innovative project that will foster collaboration within CNRM, utilizing investigators from both NIH and USU, and leverage CNRM core resources, including the Translational Imaging core, the Microscopy core, and the Preclinical Studies core. In addition, it will utilize MRI and PET applications as biomarkers for diagnosis and evaluation and investigate an intervention to promote recovery from TBI in a preclinical study, with functional, neuroimaging, and blood biomarker measures of effectiveness, which are areas of special interest.