Cyclic Nucleotide Regulation in Traumatic Brain Injury

Project: Research project

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date7/1/064/30/19

Funding

  • National Institutes of Health: $404,718.00
  • National Institutes of Health: $404,718.00
  • National Institutes of Health: $334,688.00
  • National Institutes of Health: $364,057.00
  • National Institutes of Health: $410,791.00
  • National Institutes of Health: $333,065.00
  • National Institutes of Health: $327,994.00
  • National Institutes of Health: $332,312.00
  • National Institutes of Health: $383,563.00
  • National Institutes of Health: $22,314.00
  • National Institutes of Health: $417,756.00
  • National Institutes of Health: $331,341.00

Fingerprint

Cyclic Nucleotides
Type 4 Cyclic Nucleotide Phosphodiesterase
Rolipram
Protein Isoforms
Phosphodiesterase 4 Inhibitors
Cyclic AMP-Dependent Protein Kinases
Inflammation
Therapeutics
Phosphodiesterase Inhibitors
Cyclic AMP
Traumatic Brain Injury
Brain
Brain Injuries
Percussion
Wounds and Injuries
Pathology
Brain Diseases
Alzheimer Disease
Pharmacology
Memory Disorders

ASJC

  • Medicine(all)
  • Neuroscience(all)