Combo therapy to curtail oxidative stress after TBI

描述（由申请人提供）：创伤性脑损伤（TBI）导致长期神经功能障碍。继发性神经元死亡的程度（由病理生理事件协同介导，包括但不限于炎症、氧化应激、ER应激和离子失衡）决定了TBI后的功能结果。本提案希望评估控制氧化应激和相互关联的炎症是否可以使继发性脑损伤最小化，从而改善遭受TBI的啮齿动物的神经恢复。我们将测试夹竹桃素，抑制NADPH氧化酶亚基NOX2，从而减少活性氧（ROS）的形成，和TBHQ，加强转录因子Nrf2是上游的许多抗氧化基因，从而有效地中和ROS。我们的初步数据为这2种药物在啮齿动物TBI模型中的疗效提供了原理证明。在本提案中，我们将确定2种药物的最小有效剂量和机会窗口。由于TBI后的继发性脑损伤是多因素的，通过靶向多个相互作用的通路来实现神经保护的组合疗法可能比靶向单一通路的单一疗法更有效。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，我们将测试夹竹桃麻素和TBHQ的组合是否更有效地减少TBI后的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.