Publication Date



Open access

Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Neuroscience (Medicine)

Date of Defense


First Committee Member

Coleen M. Atkins

Second Committee Member

Richard L. Rotundo

Third Committee Member

Robert W. Keane

Fourth Committee Member

Abigail S. Hackam

Fifth Committee Member

Roberta Brambilla

Sixth Committee Member

Courtney L. Robertson


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. Given the detrimental effects of the acute inflammatory response after TBI and the role of PDE4B in other models of inflammation, we hypothesized that acute PDE4B inhibition would reduce inflammation and improve cognitive and histopathological outcome after TBI. To test this hypothesis, 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. A33 treatment reduced tumor necrosis factor at 6 hrs after TBI. Treatment with A33 also reduced markers of microglial activation and neutrophil infiltration at 3 and 24 hrs after TBI, respectively. At 3 days post-injury, A33 treatment reduced cortical contusion volume. 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, the results from this study demonstrated that early treatment with a PDE4B-selective inhibitor, A33, reduced inflammation, memory deficits, cortical contusion volume and atrophy, and neuronal loss in both the pericontusional cortex and CA3 region of the hippocampus. These results suggest that acute PDE4B inhibition may be a viable treatment to reduce inflammation, pathology and memory deficits after TBI.


TBI; cAMP; PDE4B; inflammation; atrophy; memory