The Combination of Cyclosporin and Choline Optimizes Outcomes In Focal and Diffus

描述（由申请人提供）：最近在头部损伤患者中进行的几项III期临床试验（药理学和非药理学）失败，强调了改进治疗方式的必要性。人类脑外伤是一种异质性疾病，在严重程度、部位、病因、临床表现和神经病理学上有很大不同。这与实验性脑损伤研究不同，在实验性脑损伤研究中，多个变量被仔细控制。创伤性脑损伤后的急慢性分子、细胞、生化和病理生理事件是复杂的、多因素的。可能没有一种“灵丹妙药”能够完全成功地预防脑损伤后的二次损伤。相反，针对继发性病理的特定窗口的组合药物治疗可能比单一药物治疗更有效。在拟议的实验中，pi将评估TBI和环孢素A （CsA）管理后的细胞和功能结果，然后补充膳食胆碱。CsA和胆碱联合用药的选择是基于这些药物的临床效用、之前发表的研究成果以及Pauly/Scheff/Sullivan实验室产生的初步数据。该建议的总体假设是，与单一或双重治疗方式相比，组合方法将优化结果。这些实验将促进对创伤性脑损伤的神经生物学后果的理解，并确定药物/行为联合方法对两种不同脑损伤模型的康复效果。所提出的结果测量将为TBI后的神经生物学结果提供重要的新信息。创伤性脑损伤的动物研究通常不采用联合治疗方法。然而，考虑到人类脑损伤的可变性和复杂性，针对特定神经病理事件使用多种药物的治疗策略似乎是一种可能优化结果的实用方法。本研究提出的研究具有重要意义，可以增加我们对创伤性脑损伤个体的病理生理学和治疗治疗的理解。如果研究显示CsA和胆碱联合使用有益，那么pi将与临床研究人员会面，看看这是否可能是一项新的试验或正在考虑资助的CsA试验的附加试验。虽然提出的药理学实验不是特别的机制，但它们是可行的，并直接转化为人类患者。美国国立卫生研究院的路线图认为，如果治疗方法可以直接应用于人类，那么机制研究就不是首要任务。本实验采用两种不同的大鼠脑损伤模型：局灶性损伤的皮质挫伤模型和弥漫性损伤的内侧液击模型。与之前使用的CCI或MFPI模型相比，pi将测试的综合结果测量可以更好地描述采收率。最后，在认知方面的功能恢复是这项资助的主要焦点。这些研究具有转译性，因为环孢素和胆碱都被批准用于人类患者。然而，动物方面的文献还存在空白，特别是关于CsA对认知恢复的影响。胆碱很容易获得，可以在重症监护环境以外的TBI患者中使用。创伤性脑损伤的动物研究通常不采用联合治疗方法。然而，考虑到人类脑损伤的可变性和复杂性，针对特定神经病理事件使用多种药物的治疗策略似乎是一种可能优化结果的实用方法。

DESCRIPTION (provided by applicant): The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with head injury underscores the need for improved therapeutic modalities. TBI in humans is a heterogeneous condition that differs substantially in severity, location, etiology, clinical presentation and neuropathology. This differs from experimental TBI studies where multiple variables are carefully controlled. The acute and chronic molecular, cellular, biochemical and pathophysiological events that follow TBI are complex and multi-factorial. There may not be a single "magic bullet" drug that will be completely successful in preventing secondary damage following brain injury. Rather, combinatorial drug treatments that target specific windows of secondary pathology may be more efficacious than treatment with a single drug. In the proposed experiments, the PIs will evaluate cellular and functional outcomes following TBI and administration of Cyclosporin A (CsA), followed by dietary choline supplementation. The combination of CsA and choline was chosen based on the clinical utility of these drugs, previously published work, and preliminary data generated by the Pauly/Scheff/Sullivan labs. The overall hypothesis of this proposal is that a combinatorial approach will optimize outcome compared to single or dual treatment modalities. The experiments will advance the understanding of the neurobiological consequences of TBI and determine the efficacy of a combined pharmacological/behavioral approach to recovery in two different models of brain injury. The outcome measures proposed will provide important new information about neurobiological outcomes following TBI. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However, given the variability and complexity of human brain injuries, a treatment strategy that uses multiple agents, targeted at specific neuropathological events, seems to be a pragmatic approach that may optimize outcome. The studies proposed for this research are highly significant and could add to our understanding of the pathophysiology and therapeutic treatment of individuals with traumatic brain injuries. If the studies show benefit of combining CsA and choline, the PIs will meet with clinical investigators to see if this could possibly be a new trial or an add-on to the CsA trial under consideration for funding. Although the pharmacological experiments proposed are not particularly mechanistic, they are feasible and directly translatable into human patients. The NIH road map contends that if therapeutics are directly translatable to humans, mechanistic studies are not the initial priority. Two different models of rat TBI will be used in these experiments, the cortical contusion model of focal injury, and the medial fluid percussion model of diffuse injury. The combined outcome measure the PIs will test may provide better characterization of recovery than previously used in either the CCI or MFPI model. Finally, functional recovery in terms of cognition is a major focus of this grant. These studies are translational since both cyclosporin and choline are both approved for use in human patients. However, the animal literature has gaps, especially for the effects of CsA on cognitive recovery. Choline is readily available and could be administered to TBI patients outside of a critical care setting. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However, given the variability and complexity of human brain injuries, a treatment strategy that uses multiple agents, targeted at specific neuropathological events, seems to be a pragmatic approach that may optimize outcome. PUBLIC HEALTH RELEVANCE: The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with traumatic brain injury (TBI) underscores the need for improved therapeutic modalities. The overall hypothesis of this proposal is that a combinatorial approach with cyclosporin A (CsA) and dietary choline supplementation will optimize outcome compared to single treatment modalities. CsA and choline are both approved by the FDA and actively being pursued in NIH-sponsored trials as monotherapy for human TBI patients. The PIs' hypothesis will be evaluated in two different models of rat TBI that have different mechanisms and timing of neuropathology. These studies are a logical extension of current trials in TBI, and will use a set of testable hypotheses to provide clinically relevant information about this drug combination.