Mitochondria as a target for protection against hypoxic-ischemic brain injury

描述（由申请人提供）：据估计，每年有120万婴儿死于出生窒息及其并发症——缺氧缺血性脑损伤。在美国，新生儿hi脑损伤仍然是儿童终身神经功能障碍的主要原因之一。这表明迫切需要在更好地理解脑发育中HI损伤机制的基础上制定治疗策略。线粒体功能障碍是本病中导致神经元损伤的最基本的生物学事件。虽然线粒体复合体- i （C-I）受到HI损伤的严重抑制，但在再氧合/再灌注后，C-I的能量生成功能迅速恢复。这种再灌注驱动的C-I再激活与活性氧（ROS）的产生密切相关。我们假设再灌注时线粒体C-I恢复的抑制代表了早期再灌注期间抗氧化爆发的治疗策略。我们发现，与对照组相比，暴露于C-I抑制剂的小鼠，尽管C-I相关的线粒体呼吸恢复缓慢，但吡咯哒宾表现出显著的脑损伤衰减。从这些接触吡啶虫酯的hi小鼠中分离的线粒体在再灌注过程中显示出有限的ROS生成加速。这表明，在hi后的再灌注过程中，C-I中电子传递流的恢复不仅有助于细胞恢复，而且有助于细胞损伤。具体目标旨在确定；目的1，再灌注过程中C-I恢复的抑制是否会减弱线粒体基质的氧化损伤，从而增加线粒体对ca2 +诱导的通透性过渡孔（PTP）开放的耐受性。再灌注期间的低氧血症是否会减慢线粒体C-I的再激活，以及这是否会保护大脑免受再灌注驱动的氧化应激。因此，该项目旨在建立一种针对再灌注驱动的氧化应激的C-I逐渐代谢恢复的创新治疗概念的机制原理和临床翻译。

DESCRIPTION (provided by applicant): It is estimated that 1.2 million infants die annually from birth asphyxia and its complication, hypoxic- ischemic (HI) brain injury. In U.S. neonatal HI-brain injury remains one of the major causes for a life-long neurological disability in children. This indicates an urgent need to develop therapeutic strategies based on a better understanding the mechanisms of HI injury in the developing brain. Mitochondrial dysfunction is the most fundamental biological event leading to neuronal injury in this disease. Although, mitochondrial complex-I (C-I) is severely inhibited by a HI insult, upon re-oxygenation/reperfusion the energy-generating function of C-I rapidly recovers. This reperfusion-driven re-activation of C-I is tightly linked to the generation of reactive oxygen species (ROS). We hypothesize that the inhibition of mitochondrial C-I recovery upon reperfusion represents a therapeutic strategy against an oxidative burst during early reperfusion. We show that compared to controls, mice exposed to C-I inhibitor, pyridaben exhibited significant attenuation of cerebral injury, despite a sluggish recovery of the C-I linked mitochondrial respiration. Mitochondria isolated from these pyridaben-exposed HI-mice demonstrated a limited acceleration in ROS production during reperfusion. This suggests that during reperfusion post-HI restoration of electron transport flow in the C-I contributes not only to cellular recovery, but also to cellular injury. Specific aims are designed to determine; Aim 1, whether an inhibition of the C-I recovery during reperfusion attenuates oxidative damage to mitochondrial matrix and as a result, increases mitochondrial tolerance to Ca++ induced opening of permeability transition pore (PTP). and Aim 2, whether hypoxemia during reperfusion slow down reactivation of mitochondrial C-I and whether this protects brain against reperfusion-driven oxidative stress Thus, the project is designed to establish both, mechanistic rationale and a clinical translation for an innovative therapeutic concept of a gradual metabolic recovery of the C-I directed against reperfusion-driven oxidative stress. PUBLIC HEALTH RELEVANCE: This proposal is focused to develop a novel therapeutic concept for protection of the ischemic brain against reperfusion-driven oxidative stress. Potential implication of this research is very broad, because an ischemic brain injury (stroke, hypoxic-ischemic encephalopathy) is a leading cause for neurological handicap in adults and children.