Cyclic Nucleotide Regulation in Traumatic Brain Injury

描述(申请人提供)：创伤性脑损伤(TBI)是一个重大的健康问题，每年在美国影响140万人，花费560亿美元。局灶性和弥漫性脑病变都是由脑外伤引起的，并且在最初的脑损伤后持续数小时到数天的炎症反应会加剧。不幸的是，仍然没有可用于脑外伤患者的药物治疗。这项应用的目的是确定脑外伤影响的生化信号通路，以便确定潜在的新的治疗靶点，以改善脑外伤患者的组织病理学和功能结局。我们实验室最近的工作发现，脑创伤后通过cAMP-蛋白激酶A(PKA)通路的信号转导受损。损伤皮层和海马区的cAMP水平降低，其下游靶标PKA也是如此。在其他CMS损伤模型中，磷酸二酯酶(PDE)IV抑制剂Rolipram可以防止cAMP的降解，改善神经元存活，轴突再生，并减少炎症。CAMP主要通过PKA发挥作用，众所周知，它通过抑制脑部小胶质细胞炎性细胞因子的表达和分泌来减轻炎症。因此，我们假设，脑损伤后使用PDE IV抑制剂罗利普兰治疗将通过cAMP-PKA途径改善信号传递，并通过减少炎症反应来改善组织病理学和功能结局。在目标1中，我们将确定cAMP-PKA通路在脑损伤后是否被慢性抑制，涉及哪些细胞类型，以及罗利普兰治疗是否可以挽救这一过程。临床上相关的头部损伤模型，矢状面旁中度液压冲击性脑损伤(FPI)，将被使用。在我们的初步实验中，我们观察到在FPI之前或之后给予罗利普兰治疗的皮质挫伤体积有显著的改善。此外，罗利普兰治疗提高了皮质和海马区CAS神经元的存活率。这些令人兴奋的发现促使我们在目标2中进一步评估罗利普兰的治疗时间窗口，以改善组织病理学。组织病理学的这些改善是否伴随着记忆和感觉运动缺陷的改善也将被评估。在目标3中，我们将确定罗利普兰如何通过减少炎症反应来改善功能结局的机制。以下实验旨在确定脑损伤后使用PDE IV抑制剂是否会改善cAMP-PKA途径的信号传递，改善组织病理学和认知结果，减少脑部炎症，并有望扩大我们对脑损伤患者可用的治疗方案。这些临床前研究可能为在不久的将来启动针对人类急性脑损伤的I期临床研究提供必要的数据。

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. Both focal and diffuse brain pathologies result from TBI and are exacerbated by the inflammatory response that continues from hours to days after the initial TBI. Unfortunately, there are still no pharmacological therapies available to victims suffering from TBI. The objective of this application is to identify the biochemical signaling pathways affected by TBI so that potential new therapeutic targets can be identified to improve histopatholoqical and functional outcome in people suffering from TBI. Recent work in our laboratory has found that signaling through the cAMP-protein kinase A (PKA) pathway is impaired after TBI. cAMP levels are depressed in the injured cortex and hippocampus as is its downstream target, PKA. In other models of CMS injury, the phosphodiesterase (PDE) IV inhibitor rolipram, which prevents the degradation of cAMP, improves neuronal survival, axonal regeneration, and decreases inflammation. cAMP primarily exerts its actions through PKA and is well known to reduce inflammation by inhibiting the expression and secretion of pro-inflammatory cytokines from the inflammatory cells in the brain, microglia. Thus, we hypothesize that treatment with the PDE IV inhibitor, rolipram, after TBI will improve signaling through the cAMP-PKA pathway and improve histopathological and functional outcome by decreasing the inflammatory response. In Aim 1, we will determine if the cAMP-PKA pathway is chronically depressed after TBI, what cell types are involved, and whether this can be rescued with rolipram treatment. A clinically relevant model of head injury, parasagittal moderate fluid-percussion brain injury (FPI), will be utilized. In our preliminary experiments, we observed a significant improvement in cortical contusion volume with rolipram treatment given prior to or after FPI. Furthermore, rolipram treatment improved both cortical and hippocampal CAS neuronal survival. These exciting findings have propelled us to assess further in Aim 2 the therapeutic time window for post-injury treatment of rolipram to improve histopathology. Whether these improvements in histopathology are accompanied by an improvement in memory and sensorimotor deficits will also be assessed. In Aim 3, we will determine the mechanism of how rolipram leads to an improvement in functional outcome, possibly by decreasing the inflammatory response. The following experiments are designed to determine if treatment with a PDE IV inhibitor after TBI will improve signaling through the cAMP-PKA pathway, improve histopathological and cognitive outcome, decrease inflammation in the brain, and hopefully expand our repertoire of therapies available to patients suffering from TBI. These preclinical studies could provide necessary data to initiate Phase I clinical studies in the near future, targeting acute TBI in humans.