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)转化科学和特定挑战主题，15-NS-103：神经疾病新治疗方法的“概念证明”的演示。创伤性脑损伤(TBI)是一个重大的健康问题，每年在美国影响大约140万人，造成560亿美元的损失。虽然已经进行了重要的研究来了解脑外伤的病理生理学，但目前还没有针对脑外伤患者的药物治疗方法。创伤后癫痫(PTE)发生在30%以上的中、重度颅脑损伤患者。最近的研究表明了一种新的损伤机制，即程序性坏死(坏死性下垂)，值得考虑作为颅脑损伤后药物治疗的靶点。最近，一种一流的坏死性下垂小分子抑制剂TL14077已经被鉴定出来。我们建议在临床相关的脑外伤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，当给予创伤后大鼠惊厥剂PTZ时，中度液压冲击(FP)脑损伤降低了行为和电生理改变所记录的癫痫发作阈值。此外，已发表的研究结果报告称，中度脑外伤会导致感觉运动和认知功能的长期变化。因此，我们假设，使用抗坏死性下垂分子(TL14077)治疗将减少这种创伤性侮辱的组织病理学和功能后果。在目标1中，我们将评估和优化血管内注射TL14077的量效关系和药代动力学。虽然以前的研究表明，这种小分子可以穿过血脑屏障，但在治疗研究之前，需要进行药代动力学研究，以证明吸收、分布、代谢和消除。在特定的目标2中，我们将在这个模型中确定坏死性下垂的抑制剂改变创伤损伤的分子机制的机制。具体地说，我们将评估TL14077的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(RIPK1)的激活。在目标3中，我们将评估TL14077治疗中度FP脑损伤后的组织病理学和认知后果。对于这些研究，将评估挫伤体积的组织病理学特征、选择性神经元损伤、白质病理学以及包括认知在内的行为结果测量。最后，在目标4中，将研究TL14077对PTE的影响。癫痫发作活动将通过神经兴奋的行为和电生理指标进行监测。拟议的研究得到了具有专业知识的研究人员和医疗专业人员的支持，他们使用各种必要的实验工具和结果衡量标准，以扩大我们为脑外伤患者提供的治疗方案。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脑外伤的I期临床研究提供必要的数据。在美国，创伤性脑损伤(TBI)是导致死亡和残疾的主要原因。目前还没有治疗方法来逆转脑创伤的行为后果。这项资助将测试一种针对创伤后相对较新的细胞死亡途径的新化合物是否会减少癫痫的发生率，并在临床相关的脑外伤动物模型中改善功能结果。

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.