Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury

PLoS One. 2017 May 19;12(5):e0178013. doi: 10.1371/journal.pone.0178013. eCollection 2017.


Traumatic brain injury (TBI) initiates a deleterious inflammatory response that exacerbates pathology and worsens outcome. This inflammatory response is partially mediated by a reduction in cAMP and a concomitant upregulation of cAMP-hydrolyzing phosphodiesterases (PDEs) acutely after TBI. The PDE4B subfamily, specifically PDE4B2, has been found to regulate cAMP in inflammatory cells, such as neutrophils, macrophages and microglia. To determine if PDE4B regulates inflammation and subsequent pathology after TBI, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury (2 ± 0.2 atm) and were then treated with a PDE4B - selective inhibitor, A33, or vehicle for up to 3 days post-surgery. Treatment with A33 reduced markers of microglial activation and neutrophil infiltration at 3 and 24 hrs after TBI, respectively. A33 treatment also reduced cortical contusion volume at 3 days post-injury. To determine whether this treatment paradigm attenuated TBI-induced behavioral deficits, animals were evaluated over a period of 6 weeks after surgery for forelimb placement asymmetry, contextual fear conditioning, water maze performance and spatial working memory. A33 treatment significantly improved contextual fear conditioning and water maze retention at 24 hrs post-training. However, this treatment did not rescue sensorimotor or working memory deficits. At 2 months after surgery, atrophy and neuronal loss were measured. A33 treatment significantly reduced neuronal loss in the pericontusional cortex and hippocampal CA3 region. This treatment paradigm also reduced cortical, but not hippocampal, atrophy. Overall, these results suggest that acute PDE4B inhibition may be a viable treatment to reduce inflammation, pathology and memory deficits after TBI.

MeSH terms

  • Animals
  • Brain Injuries, Traumatic / metabolism
  • Brain Injuries, Traumatic / pathology
  • Brain Injuries, Traumatic / prevention & control*
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Male
  • Maze Learning / drug effects*
  • Memory Disorders / drug therapy*
  • Microglia / drug effects*
  • Microglia / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley


  • Pyrimidines
  • Cyclic AMP
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, rat