Efficacy of Necrostatins on Posttraumatic Epilepsy

描述（由申请人提供）： 本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- NS-103：神经系统疾病新治疗方法的“概念证明”演示。创伤性脑损伤（TBI）是一个重大的健康问题，每年影响美国约140万人，耗资560亿美元。虽然已经进行了大量的研究来了解TBI的病理生理学，但目前没有药物治疗可用于患有TBI的受害者。超过30%的中度或重度TBI患者发生创伤后癫痫（PTE）。最近的研究表明，一种新的损伤机制被鉴定为程序性坏死（坏死性凋亡），值得考虑作为TBI后药物治疗的靶点。最近，人们发现了第一种坏死性凋亡小分子抑制剂TL 14077。我们建议在临床相关的TBI模型中评估该化合物的神经保护和抗癫痫特性。我们实验室最近的工作表明，中度液压冲击（FP）脑损伤降低癫痫发作的阈值记录的行为以及电生理变化时，惊厥剂PTZ给予创伤后大鼠。此外，已发表的研究结果报告称，中度TBI会导致感觉运动和认知功能的长期改变。因此，我们假设用抗坏死性凋亡分子（TL 14077）治疗将减少这种创伤性损伤的组织病理学以及功能后果。在目标1中，我们将通过血管内输注评价和优化TL 14077的剂量-反应疗效和药代动力学。虽然先前的研究已经表明这种小分子穿过血脑屏障，但在治疗研究之前需要进行药代动力学研究以记录吸收、分布、代谢和消除。在具体目标2中，我们将确定坏死性凋亡抑制剂改变该模型中创伤性损伤的分子机制的机制。具体而言，我们将评估TL 14077治疗是否会抑制创伤诱导的脆弱脑区受体相互作用蛋白激酶1（RIPK 1）活性的激活。在目标3中，我们将评估中度FP脑损伤后TL 14077治疗的组织病理学和认知后果。对于这些研究，将评价挫伤体积的组织病理学表征、选择性神经元损伤、白色物质病理学沿着行为结局指标（包括认知）。最后，在目标4中，将研究TL 14077对PTE的影响。将通过神经元兴奋的行为和电生理指标监测癫痫发作活动。拟议的研究得到了研究人员和医疗专业人员的支持，他们拥有使用各种实验工具和必要的结果测量的专业知识，以扩大我们对TBI患者的治疗方案。重要的是，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。创伤性脑损伤（TBI）是美国死亡和残疾的主要原因。目前还没有治疗方法可以逆转脑外伤的行为后果。这项资助将测试一种针对创伤后相对新的细胞死亡途径的新型化合物是否会降低癫痫的发生率，并改善临床相关的TBI动物模型的功能结果。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- NS-103: Demonstration of "Proof of Concept" for a New Therapeutic Approach in a Neurological Disease. Traumatic brain injury (TBI) is a significant health concern, affecting approximately 1.4 million people in the United States each year at a cost of $56 billion. Although significant research has been conducted to understand the pathophysiology of TBI, no pharmacological therapies are currently available to victims suffering from TBI. Posttraumatic epilepsy (PTE) occurs in over 30% of patients with moderate or severe TBI. Recent studies have implicated a novel injury mechanism identified as programmed necrosis (necroptosis) that merits consideration as a target for pharmacotherapy after TBI. Recently, a first in class small molecule inhibitor of necroptosis, TL14077 has been identified. We propose to evaluate the neuroprotective and anti- epileptic properties of this compound in a clinically relevant model of TBI. Recent work in our laboratory has shown that moderate fluid percussion (FP) brain injury reduces the threshold for seizures documented by both behavioral as well as electrophysiological changes when the convulsive agent PTZ is given to posttraumatic rats. Also, published findings reported that moderate TBI leads to long term alterations in sensorimotor as well as cognitive function. Thus, we hypothesize that treatment with an anti-necroptosis molecule (TL14077) will reduce the histopathological as well as functional consequences of this traumatic insult. In Aim 1, we will evaluate and optimize the dose-response efficacy and pharmokinetics of TL14077 by intravascular infusion. While previous studies have shown that this small molecule crosses the blood-brain barrier, pharmokinetic studies to document absorption, distribution, metabolism and elimination are required prior to the treatment studies. In Specific Aim 2, we will determine mechanisms by which inhibitors of necroptosis alter molecular mechanisms of traumatic injury in this model. Specifically, we will assess whether treatment with TL14077 will inhibit trauma-induced activation of receptor-interacting protein kinase 1 (RIPK1) activity in vulnerable brain regions. In Aim 3, we will assess the histopathological and cognitive consequences of TL14077 treatment following moderate FP brain injury. For these studies, histopathological characterization of contusion volume, selective neuronal damage, white matter pathology along with behavioral outcome measures including cognition will be evaluated. Finally, in Aim 4, the effects of TL14077 on PTE will be investigated. Seizure activity will be monitored by behavioral and electrophysiological indicators of neuronal excitation. The proposed studies are supported by investigators and medical professionals with expertise using the various experimental tools and outcome measures necessary to expand our repertoire of therapies available to patients suffering from TBI. Importantly, these preclinical studies could provide necessary data to initiate Phase I clinical studies in the near future targeting acute TBI in humans. Traumatic brain injury (TBI) is a major cause of death and disability in the United States. There are currently no treatments to reverse the behavioral consequences of brain trauma. This grant will test whether a novel compound targeting a relatively new pathway of cell death after trauma will reduce the incidence of epilepsy and improve functional outcome in a clinically relevant animal model of TBI.