Cyclic Nucleotide Regulation in Traumatic Brain Injury

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。局灶性和弥漫性脑病变都是由TBI引起的，并且在初始TBI后持续数小时至数天的炎症反应会加重。不幸的是，对于创伤性脑损伤的受害者，仍然没有可用的药物治疗方法。本应用程序的目的是确定受TBI影响的生化信号通路，以便确定潜在的新治疗靶点，以改善TBI患者的组织病理学和功能结果。我们实验室最近的工作发现，通过camp -蛋白激酶A （PKA）途径的信号通路在TBI后受损。损伤后的皮质和海马中cAMP水平下降，其下游靶点PKA也下降。在其他CMS损伤模型中，磷酸二酯酶（PDE） IV抑制剂罗利普兰可以阻止cAMP的降解，提高神经元存活，轴突再生，减少炎症。cAMP主要通过PKA发挥作用，众所周知，它通过抑制大脑小胶质细胞炎症细胞的促炎细胞因子的表达和分泌来减轻炎症。因此，我们假设TBI后使用PDE IV抑制剂罗利普兰治疗可以改善cAMP-PKA通路的信号传导，并通过减少炎症反应改善组织病理学和功能结果。在Aim 1中，我们将确定创伤性脑损伤后cAMP-PKA通路是否被慢性抑制，涉及哪些细胞类型，以及是否可以通过罗利普兰治疗来挽救。将采用临床相关的头部损伤模型，矢状旁中度液体冲击脑损伤（FPI）。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可以显著改善皮质挫伤体积。此外，罗利普兰治疗可改善皮质和海马CAS神经元的存活。这些令人兴奋的发现促使我们在Aim 2中进一步评估罗利普兰损伤后治疗的治疗时间窗，以改善组织病理学。这些组织病理学上的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Aim 3中，我们将确定罗利普兰如何改善功能结果的机制，可能是通过减少炎症反应。以下实验旨在确定创伤性脑损伤后使用PDE IV抑制剂治疗是否会改善cAMP-PKA通路的信号传导，改善组织病理学和认知结果，减少大脑炎症，并有望扩大我们对创伤性脑损伤患者的治疗方案。这些临床前研究可以为在不久的将来启动针对人类急性TBI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.