Every year an estimated 1.7 million people suffer a traumatic brain injury (TBI). The inflammatory response triggered by the TBI increases neuronal death and worsens outcome. An important mediator of this inflammatory response is the pro-inflammatory cytokine, tumor necrosis factor (TNF). The negative consequences of TNF are primarily attributed to its signaling through TNF receptor 1 (TNFR1). Accordingly, TNFR1 knockout mice have improved histopathological and functional outcome after TBI. After TBI, TNF expression can be attenuated by pharmacological elevation of cAMP;this is accomplished by inhibitors that target the cAMP-hydrolyzing enzyme, phosphodiesterase 4 (PDE4). The anti-inflammatory effects of PDE4 inhibition are primarily attributed to the PDE4B subfamily. In other models of inflammation, knocking out or inhibiting PDE4B significantly reduces TNF production and neutrophil recruitment. Our preliminary data found that a novel PDE4B inhibitor improves histopathology at 3 days after TBI. Furthermore, my preliminary data found that the PDE4B isoform, PDE4B2, is elevated in microglia and present in infiltrating leukocytes at 24 hrs after TBI. Thus, my central hypothesis is that acute PDE4B inhibition improves cognitive and histopathological outcome after TBI through the attenuation of pro-inflammatory TNF signaling. To test this hypothesis this study will be divided into four aims.
The first aim will address whether induced expression of PDE4B2 after TBI colocalizes with TNF.
The second aim will determine whether a PDE4B inhibitor attenuates TNF production and neutrophil recruitment after TBI.
The third aim will determine whether inhibiting PDE4B reduces histopathology and learning and memory deficits after TBI.
The fourth aim will address whether a PDE4B inhibitor improves outcome after TBI through its effects on TNFR1 signaling;this will be accomplished through the use of TNFR1 knockout mice. Overall, the results from this study will determine the importance of PDE4B inhibition as a therapeutic strategy for TBI.
Every year 1.7 million people suffer a traumatic brain injury in the United States. The inflammatory response triggered by the initial brain trauma increases neuronal death and worsens outcome. This proposal will establish the therapeutic potential of a novel anti-inflammatory drug for the treatment of traumatic brain injury.