Neonatal hypoxia/ischemia is a known cause of cerebral damage resulting from inadequate blood flow and/or oxygen delivery to the infant brain before, during, or after birth. The occurrence among hospital deliveries is ~2-4 per 1000 full-term births with a drastic increase among premature newborns. The deficit in oxygen delivery to the brain results in extensive damage and severe disabilities. Restoration of blood flow critical for salvage of ischemic tissue, however, also causes significant cerebral damage due in part to cytotoxic reactive oxygen species (ROS) generated upon reintroduction of oxygen. The current standard treatment for neonatal hypoxia/ischemia is therapeutic hypothermia applied on average 4-6 hours after restoration of blood flow/oxygen delivery. A safe and effective neuroprotective intervention that specifically targets reperfusion injury during the early phase of reoxygenation would fill a critical unmet need in the treatment of infants exposed to hypoxia/ischemia. Our molecular studies on mitochondrial function uncovered a novel method to prevent ROS generation during early reoxygenation. Indeed, our studies have, for the first time: (i) identified two wavelengths of infrared light (IRL) that specifically and reversibly reduce mitochondrial respiration by acting on cytochrome c oxidase; and (ii) documented that IRL, applied at the time of reoxygenation, is neuroprotective and limits ROS generation. Based on these data, we propose develop iNeuroLUX, a device that will safely deliver therapeutic IRL to the infant brain. To achieve this goal, Phase I will propose 2 experimental aims: ? Conduct ex vivo molecular investigation to define the safe therapeutic IRL dose that can be applied in our large animal studies (Aim 1). ? Establish the effect of IRL on HIE in a large animal model of neonatal hypoxia/ischemia (Aim 2). We will determine the effects of IRL on neurologic damage in a neonate swine model of hypoxia/ischemia and investigate safety of IRL in undamaged tissues. Phase II will build upon the findings in the first phase and: ? Design and construct a iNeuroLUX light-delivery prototype for testing IRL therapy (Aim 3). ? Establish the efficacy of iNeuroLUX and evaluate the concept of iNeuroLUX combination therapy with hypothermia (Aim 4). ? Document critical safety parameters of iNeuroLUX to move forward with FDA approval (Aim 5). This proposal combines multi-disciplinary expertise, compelling preliminary data, and state-of-the-art resources available to our research team to address a highly significant health problem.
Delivery of newborns is sometimes accompanied by complications that cause a reduction in blood flow or oxygen delivery to their brain, resulting in brain damage and disorders such as epilepsy and cerebral palsy. Restoration of oxygen back to the brain also worsens brain damage by generating highly toxic agents called free radicals. We have discovered that treatment with specific wavelengths of infrared light, applied non-invasively at the time when blood flow is restored to the brain, substantially reduces the production of free radicals and brain damage, and we propose to develop this therapy for a clinical treatment for newborns.
|Kalpage, Hasini A; Bazylianska, Viktoriia; Recanati, Maurice A et al. (2018) Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J :fj201801417R|