Modulation of the Cyclic AMP Pathway after Traumatic Brain Injury in Aged Animals

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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. The highest rates of hospitalization and death from TBI occur in the elderly ages 75 or older; and as our population ages, brain trauma in the elderly will become an even more significant health problem. Currently, there are no pharmacological therapies available to elderly people suffering from TBI because of the lack of studies identifying the biochemical changes that are misregulated after TBI. The overall goal of the current application is to elucidate the biochemical signaling pathways that are altered during TBI in the aged animal so that new potential therapeutic targets can be identified to improve functional outcome in aged individuals after brain trauma. Using the parasagittal fluid-percussion head injury (FPI) as a clinically relevant model of TBI, we have found that signaling through the cAMP-protein kinase A (PKA) pathway is impaired after TBI. In both young adult and aged animals, cAMP levels are decreased after TBI. Furthermore, in young adult animals, activation of cAMP-dependent signaling remains chronically impaired for up to 12 weeks after TBI. In Aim 1, we will determine if cAMP and PKA signaling is impaired after TBI in aged animals as compared to young adult animals. In uninjured aged animals, deficits exist already in the ability to increase cAMP levels and activate PKA during learning. Treatment with a phosphodiesterase (PDE) inhibitor, rolipram, to increase cAMP levels improves hippocampal synaptic plasticity and learning in the uninjured aged animal. Our preliminary data indicate that rolipram can rescue the decreases in cAMP levels in the aged animal after TBI. Thus, we hypothesize that treatment with rolipram after TBI will improve signaling through the cAMP-PKA pathway and improve outcome in aged animals. In Aim 2, we will determine if rolipram improves histopathological outcome after TBI in aged animals. A prominent disability after TBI is cognitive dysfunction and in particular, memory formation. The cortex and hippocampus are highly vulnerable during TBI which affects the ability to form and store memories. In Aim 3, we will determine if rolipram improves cAMP- dependent signaling in acute hippocampal slices and ameliorates hippocampal-dependent learning deficits after TBI in aged animals. These proposed studies will identify the biochemical mechanisms misregulated by trauma in the aged brain and expand the potential therapeutic interventions available to elderly patients suffering from brain trauma to improve cognition and facilitate recovery. PUBLIC HEALTH RELEVANCE: More than 1.4 million individuals per year are afflicted with a traumatic brain injury (TBI) and the ability to withstand brain injury diminishes with age. The research proposed in this grant application is to develop a therapy that reduces pathology in the brain after TBI and improves behavioral recovery in the aged population.