Traumatic brain injury (TBI) is a significant health concern, affecting 1.4 million people in the United States each year at a cost of $56 billion. Both focal and diffuse brain pathologies result from TBI and are exacerbated by the inflammatory response that continues from hours to days after the initial TBI. Unfortunately, there are still no pharmacological therapies available to victims suffering from TBI. The objective of this application is to identify the biochemical signaling pathways affected by TBI so that potential new therapeutic targets can be identified to improve histopatholoqical and functional outcome in people suffering from TBI. Recent work in our laboratory has found that signaling through the cAMP-protein kinase A (PKA) pathway is impaired after TBI. cAMP levels are depressed in the injured cortex and hippocampus as is its downstream target, PKA. In other models of CMS injury, the phosphodiesterase (PDE) IV inhibitor rolipram, which prevents the degradation of cAMP, improves neuronal survival, axonal regeneration, and decreases inflammation. cAMP primarily exerts its actions through PKA and is well known to reduce inflammation by inhibiting the expression and secretion of pro-inflammatory cytokines from the inflammatory cells in the brain, microglia. Thus, we hypothesize that treatment with the PDE IV inhibitor, rolipram, after TBI will improve signaling through the cAMP-PKA pathway and improve histopathological and functional outcome by decreasing the inflammatory response.
In Aim 1, we will determine if the cAMP-PKA pathway is chronically depressed after TBI, what cell types are involved, and whether this can be rescued with rolipram treatment. A clinically relevant model of head injury, parasagittal moderate fluid-percussion brain injury (FPI), will be utilized. In our preliminary experiments, we observed a significant improvement in cortical contusion volume with rolipram treatment given prior to or after FPI. Furthermore, rolipram treatment improved both cortical and hippocampal CAS neuronal survival. These exciting findings have propelled us to assess further in Aim 2 the therapeutic time window for post-injury treatment of rolipram to improve histopathology. Whether these improvements in histopathology are accompanied by an improvement in memory and sensorimotor deficits will also be assessed.
In Aim 3, we will determine the mechanism of how rolipram leads to an improvement in functional outcome, possibly by decreasing the inflammatory response. The following experiments are designed to determine if treatment with a PDE IV inhibitor after TBI will improve signaling through the cAMP-PKA pathway, improve histopathological and cognitive outcome, decrease inflammation in the brain, and hopefully expand our repertoire of therapies available to patients suffering from TBI. These preclinical studies could provide necessary data to initiate Phase I clinical studies in the near future, targeting acute TBI in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056072-05
Application #
8026009
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2007-03-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2011
Total Cost
$327,994
Indirect Cost
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
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Wilson, Nicole M; Gurney, Mark E; Dietrich, W Dalton et al. (2017) Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury. PLoS One 12:e0178013
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Titus, David J; Wilson, Nicole M; Freund, Julie E et al. (2016) Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor. J Neurosci 36:7095-108
Ghosh, Mousumi; Aguirre, Vladimir; Wai, Khine et al. (2015) The interplay between cyclic AMP, MAPK, and NF-?B pathways in response to proinflammatory signals in microglia. Biomed Res Int 2015:308461
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Atkins, Coleen M; Cepero, Maria L; Kang, Yuan et al. (2013) Effects of early rolipram treatment on histopathological outcome after controlled cortical impact injury in mice. Neurosci Lett 532:1-6
Titus, D J; Furones, C; Kang, Y et al. (2013) Age-dependent alterations in cAMP signaling contribute to synaptic plasticity deficits following traumatic brain injury. Neuroscience 231:182-94

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