Effects of intranasal insulin on cortical & hippocampal injury following TBI

TBI affects approximately 1.5 million Americans annually and causes serious health problems lasting long after the acute injury. This is experienced in the military through conventional trauma away from combat (like car accidents, fights, extreme sport injuries, etc.) and through blast related injuries. Injured tissue from TBI includes damage to the cortex through direct contact with the skull, shearing forces, or an object penetrating the skull. TBI also often leads to damage of the hippocampus, reflected as neural loss and atrophy, and linked to mood disorders and memory dysfunction. Currently, there is no effective treatment for these deficits that develop after mild to moderate TBI.
Neuron damage and loss in the hippocampus after TBI can result from fluxuations in metabolic processes, wherein the injured brain experiences first a marked increase in glucose uptake followed by a chronic reduction. These changes in glucose uptake and use are associated with negative long term outcomes. To date, there are no treatments available clinically to address these changes in glucose uptake. However, we and others have shown that administration of insulin will improve outcomes after TBI. Administration of insulin through the nose (intranasal) will allow for insulin to be absorbed directly into the brain (by the olfactory or trigeminal nerves), avoiding negative effects on blood glucose and allowing insulin to pass the blood-brain barrier. Our laboratory has shown that intranasal insulin improves glucose uptake, memory function and reduces inflammation in the hippocampus. However, the mechanism of these effects, such as whether they are mediated by the insulin receptor, whether they are specific for the hippocampus or function in other regions of the brain, and whether they are mediated by neurons or by immune cells in the brain, is unknown. The purpose of this study is therefore to evaluate the mechanism of intranasal insulin administration and broaden its therapeutic potential for treatment of TBI in a rat model. We hypothesize that intranasal insulin administration will decrease hippocampal but not cortical neuronal damage and death and microglial inflammation after traumatic brain injury. To test this hypothesis, we propose the following three specific aims:
1. Aim 1. To determine the effect of intranasal insulin on cortical neuronal viability.
2. Aim 2. To demonstrate that intranasal insulin improves hippocampal neuronal viability.
3. Aim 3. To assess microglial changes in the cortex and hippocampus after intranasal insulin administration.
Previous research has demonstrated that intranasal insulin improves outcome after TBI. This proposal will help to clarify the mechanism of these effects and provide more information on therapeutic targets. These data will be essential to the development of a future clinical trial, and will fall under the Force Health Protection research priority of the TriService Nursing Research Program (TSNRP). As a certified registered nurse anesthetist (CRNA) stationed at Landstuhl Army Medical Center in Landstuhl, Germany, I was immersed in the severity of the casualties of the wars in Iraq and Afghanistan. For much of the time there I treated severe blast injuries on a daily basis. I saw first-hand the impact these horrible injuries that included missing limbs, severe burns, and head injuries that often required craniotomies, bolts, or other life saving measures. Prior to serving as a CRNA, I served as an ER/ICU nurse and an educator in a school of nursing. In these arenas, I often witnessed and/or discussed the impact of head injuries. Working in a Neuro Intensive Care Unit (NICU) I saw the impact these injuries had on the patient who would never be able to take care of himself again, the wife that would now have to take care of him for the rest of his life instead of living her own, and the system that would have to support him. If a treatment as simple as the administration of insulin could improve this situation, it would not only be the patient that benefits. This research could lead to an easily portable, easy to administer, noninvasive treatment with little to no side effects that has the potential to impact the quality of life of any soldier, sailor, airman, marine…or civilian.