Traumatic brain injury (TBI) is a significant health concern affecting 1.4 million people in the United States. Although much is known about the pathophysiological mechanisms underlying TBI, few therapeutic strategies have been successfully translated to the clinical setting. TBI initiates multiple injury cascades in the brain including inflammatory processes that exacerbate the initial injury. Our laboratory has found that post- traumatic temperature manipulations can dramatically attenuate trauma-induced inflammatory processes and significantly improve outcome after TBI. Mild to moderate hypothermia reduces the infiltration of inflammatory cells into the injured brain and attenuates elevations of the pro-inflammatory cytokine, interleukin-1? (IL-1?). The overall objective of this revised application is to identify the inflammatory signaling events that are regulated by hypothermia after TBI and whether this influences clinically relevant functional outcomes.
In Aim 1 we will determine the effects of hypothermia on the formation of posttraumatic epilepsy (PTE) after TBI which occurs in as many as 1 in 4 brain-injured patients. In experimental models of epilepsy, inflammation increases in the brain as a consequence of seizures and anti-inflammatory treatments reduce seizure formation. Thus, we will assess whether hypothermia therapy after TBI modulates seizure threshold, as well as improves the histopathological and electrophysiological changes in the brain that contribute to seizure formation.
In Aim 2 we will investigate whether hypothermia therapy after TBI attenuates blood-brain barrier (BBB) permeability and the accumulation and activation of inflammatory cells in the brain such as monocyte-derived macrophages, polymorphonuclear leukocytes, microglia, and astrocytes. A new battery of BBB probes will be used to thoroughly characterize the extent to which hypothermia reduces BBB permeability.
In Aim 3 we will directly test a causal relationship between systemic and endogenous inflammatory mechanisms initiated after TBI and the development of PTE. We will also assess the effects of elevating systemic levels of IL-1? on PTE since systemic levels of pro-inflammatory cytokines are a common consequence of multi-organ trauma in the TBI patient population. This project is highly supported by an established group of investigators who provide a wealth of expertise in TBI, laboratory techniques, and temperature manipulations. This research will provide important information regarding the use of therapeutic hypothermia in both the acute and chronic injury setting. The proposed studies will provide novel information regarding the development of seizures after TBI and determine how hypothermia therapy may improve this debilitating consequence of TBI.

Public Health Relevance

Traumatic brain injury (TBI) is a major cause of death and disability in the United States. There are currently no treatments to reverse the behavioral consequences of brain trauma. This grant will test whether reducing brain temperature to 33oC after trauma will reduce the incidence of epilepsy and improve functional outcome in a clinically relevant animal model of TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042133-10
Application #
8394923
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2001-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2013
Total Cost
$316,514
Indirect Cost
$109,642
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
de Rivero Vaccari, Juan Pablo; Dietrich, W Dalton; Keane, Robert W (2014) Activation and regulation of cellular inflammasomes: gaps in our knowledge for central nervous system injury. J Cereb Blood Flow Metab 34:369-75
de Rivero Vaccari, Juan Pablo; Brand 3rd, Frank J; Sedaghat, Christina et al. (2014) RIG-1 receptor expression in the pathology of Alzheimer's disease. J Neuroinflammation 11:67
Truettner, Jessie S; Motti, Dario; Dietrich, W Dalton (2013) MicroRNA overexpression increases cortical neuronal vulnerability to injury. Brain Res 1533:122-30
Yokobori, Shoji; Bullock, Ross; Gajavelli, Shyam et al. (2013) Preoperative-induced mild hypothermia attenuates neuronal damage in a rat subdural hematoma model. Acta Neurochir Suppl 118:77-81
Yokobori, Shoji; Gajavelli, Shyam; Mondello, Stefania et al. (2013) Neuroprotective effect of preoperatively induced mild hypothermia as determined by biomarkers and histopathological estimation in a rat subdural hematoma decompression model. J Neurosurg 118:370-80
Mawhinney, Lana J; de Rivero Vaccari, Juan Pablo; Alonso, Ofelia F et al. (2012) Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain. Brain Res 1431:23-34
Bregy, Amade; Nixon, Ryan; Lotocki, George et al. (2012) Posttraumatic hypothermia increases doublecortin expressing neurons in the dentate gyrus after traumatic brain injury in the rat. Exp Neurol 233:821-8
Sakurai, Atsushi; Atkins, Coleen M; Alonso, Ofelia F et al. (2012) Mild hyperthermia worsens the neuropathological damage associated with mild traumatic brain injury in rats. J Neurotrauma 29:313-21
Bao, Ying-hui; Bramlett, Helen M; Atkins, Coleen M et al. (2011) Post-traumatic seizures exacerbate histopathological damage after fluid-percussion brain injury. J Neurotrauma 28:35-42
Lotocki, George; de Rivero Vaccari, Juan Pablo; de Rivero Vaccari, Juan et al. (2011) Oligodendrocyte vulnerability following traumatic brain injury in rats. Neurosci Lett 499:143-8

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