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

描述（由申请人提供）：创伤性脑损伤（TBI）是一个重大的健康问题，每年影响美国140万人，耗资560亿美元。TBI住院率和死亡率最高的是75岁及以上的老年人；随着人口老龄化，老年人的脑外伤将成为一个更加严重的健康问题。目前，由于缺乏研究确定脑外伤后失调的生化变化，尚无针对老年脑外伤患者的药物治疗方法。当前应用的总体目标是阐明老年动物脑外伤期间改变的生化信号通路，从而确定新的潜在治疗靶点，以改善老年脑外伤患者的功能结局。我们将矢状旁液体撞击头部损伤（FPI）作为TBI的临床相关模型，发现通过camp -蛋白激酶a （PKA）途径的信号通路在TBI后受损。在年轻成年动物和老年动物中，脑外伤后cAMP水平均下降。此外，在年轻的成年动物中，camp依赖性信号的激活在脑外伤后12周内仍会长期受损。在Aim 1中，我们将确定与年轻成年动物相比，老年动物脑外伤后cAMP和PKA信号是否受损。在未受伤的年老动物中，在学习过程中增加cAMP水平和激活PKA的能力已经存在缺陷。用磷酸二酯酶（PDE）抑制剂罗利普兰（rolipram）增加cAMP水平，可改善未受伤老年动物海马突触可塑性和学习能力。我们的初步数据表明，罗利普兰可以挽救老年动物脑外伤后cAMP水平的下降。因此，我们假设脑外伤后用罗利普兰治疗可以改善cAMP-PKA通路的信号传导，改善老年动物的预后。在Aim 2中，我们将确定罗利普兰是否能改善老年动物脑外伤后的组织病理学结果。脑外伤后最显著的残疾是认知功能障碍，尤其是记忆形成障碍。脑外伤时，大脑皮层和海马体非常脆弱，会影响记忆的形成和储存能力。在Aim 3中，我们将确定罗利普兰是否改善急性海马切片中cAMP依赖的信号，并改善老年动物脑外伤后海马依赖的学习缺陷。这些建议的研究将确定老年脑外伤失调的生化机制，并扩大潜在的治疗干预措施，以改善老年脑外伤患者的认知和促进康复。公共卫生相关性：每年有超过140万人遭受创伤性脑损伤（TBI）的折磨，并且承受脑损伤的能力随着年龄的增长而下降。这项拨款申请中提出的研究是开发一种治疗方法，减少脑外伤后的脑部病理，改善老年人的行为恢复。

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.