Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor.

摘要: Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there no effective treatments to improve TBI-induced learning impairments. TBI results decreased cAMP signaling reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved memory. also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates by hydrolyzing cAMP. We hypothesized that subtype-selective PDE4B inhibitor could reverse the deficits induced TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion injury. At 3 months postsurgery, animals were administered selective vehicle before cue contextual fear conditioning, water maze training spatial working task. Treatment with significantly reversed conditioning retention. further understand underlying mechanisms of these impairments, we examined hippocampal long-term potentiation (LTP). resulted significant reduction basal synaptic transmission impaired expression LTP. rescued LTP expression. The tumor necrosis factor-α levels increased phosphorylated CREB after TBI, suggesting drug inhibited molecular pathways known be regulated PDE4B. These suggest is potential therapeutic chronic dysfunction plasticity following SIGNIFICANCE STATEMENT Currently, an estimated 3.2–5.3 million individuals living disabilities from United States, 8 10 report cognitive (Thurman et al., 1999; Lew 2006; Zaloshnja 2008). One associated hippocampus. In study, 4B (PDE4B) reduces rescues potentiation. inhibition has ability overall functioning for people