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理都是由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剧。不幸的是，仍然没有药物治疗可用于TBI患者。本申请的目的是鉴定受TBI影响的生物化学信号传导途径，以便可以鉴定潜在的新治疗靶点，以改善患有TBI的人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）途径的信号转导在TBI后受损。cAMP水平在受损的皮质和海马中被抑制，其下游靶标PKA也是如此。在CMS损伤的其他模型中，磷酸二酯酶（PDE）IV抑制剂咯利普兰（rolipram）可防止cAMP降解，改善神经元存活、轴突再生并减少炎症。cAMP主要通过PKA发挥其作用，并且众所周知通过抑制促炎细胞因子从脑中的炎性细胞（小胶质细胞）的表达和分泌来减少炎症。因此，我们假设TBI后用PDE IV抑制剂咯利普兰治疗将改善通过cAMP-PKA途径的信号传导，并通过减少炎症反应改善组织病理学和功能结果。在目标1中，我们将确定cAMP-PKA通路是否在TBI后被长期抑制，涉及哪些细胞类型，以及这是否可以用咯利普兰治疗来挽救。将使用临床相关的头部损伤模型，即脑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之前或之后给予咯利普兰治疗的皮质挫伤体积的显著改善。此外，咯利普兰治疗改善皮质和海马CAS神经元的存活。这些令人兴奋的发现促使我们在目标2中进一步评估咯利普兰用于损伤后治疗以改善组织病理学的治疗时间窗。还将评估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。在目标3中，我们将确定咯利普兰如何导致功能结局改善的机制，可能是通过减少炎症反应。以下实验旨在确定TBI后用PDE IV抑制剂治疗是否会改善通过cAMP-PKA途径的信号传导，改善组织病理学和认知结果，减少脑中的炎症，并有望扩大我们对TBI患者可用的治疗方案。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.