Combo therapy to curtail oxidative stress after TBI

描述(申请人提供)：创伤性脑损伤(TBI)导致长期的神经功能障碍。继发性神经元死亡的程度(由包括但不限于炎症、氧化应激、内质网应激和离子失衡的病理生理事件协同介导)决定了脑外伤后的功能结果。目前的建议希望评估控制氧化应激和相互关联的炎症是否可以最大限度地减少继发性脑损伤，从而改善脑外伤后啮齿动物的神经恢复。我们将测试apocynin，它抑制NADPH氧化酶亚基NOX2，从而减少活性氧物种(ROS)的形成，以及TBHQ，它增强转录因子Nrf2，它位于许多抗氧化基因的上游，从而有效地中和ROS。我们的初步数据为这两种药物在啮齿动物脑外伤模型中的疗效提供了原理上的证据。在这项提案中，我们将确定这两种药物的最小有效剂量和机会窗口。由于颅脑损伤后继发性脑损伤是多因素的，通过靶向多个相互作用的路径来实现神经保护的联合治疗可能比针对单一路径的单一治疗更有效。为了有效地控制氧化应激，必须减少ROS的形成，同时增加ROS的处置。因此，我们将测试apocynin和TBHQ的联合应用是否能更有效地减少脑损伤后神经元死亡和神经功能障碍。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) leads to long-term neurological dysfunction. The extent of secondary neuronal death (mediated synergistically by pathophysiologic events that include but not limited to inflammation, oxidative stress, ER stress and ionic imbalance) dictates the functional outcome after TBI. The present proposal wishes to evaluate if controlling oxidative stress and the interconnected inflammation can minimize the secondary brain damage leading to improved neurological recovery in rodents subjected to TBI. We will test apocynin that inhibits NADPH oxidase subunit NOX2 and thus curtails reactive oxygen species (ROS) formation, and TBHQ that potentiates the transcription factor Nrf2 which is upstream to many antioxidant genes and thus efficiently neutralizes ROS. Our preliminary data provided the proof-of-principle for the efficacy of these 2 drugs in a rodent TBI model. In this proposal we will identify the minimal efficacious dose and the window of opportunity for the 2 drugs. As secondary brain damage after TBI is multifactorial, a combination therapy to achieve neuroprotection by targeting multiple interactive pathways might be more efficacious than mono-therapies that target single pathways. To efficiently control oxidative stress, it is essential to curtail the formation of ROS and at the same time increase the disposal of ROS. Hence, we will test if a combination of apocynin and TBHQ curtails neuronal death and neurological dysfunction after TBI more effectively.