Non-invasive mitochondrial modulation therapy for ischemic stroke

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Summary: Ischemic stroke is a leading cause of death and long-term disability in the US. The current gold standard for the treatment of ischemia-reperfusion injury in the setting of focal brain ischemia is restoration of blood flow with recanalization. However, a substantial portion of the damage caused by ischemia/reperfusion occurs during the reperfusion phase: as ischemic tissue is reoxygenated, reactive oxygen species (ROS) are quickly generated, starting early during reflow. Reperfusion injury has proved difficult to treat pharmacologically, likely because effective drug concentrations have not built up sufficiently during the early phase of reperfusion. The mitochondrial electron transport chain (ETC) is a major site of ROS production during cellular stress due to ETC hyper-activation, which causes high mitochondrial membrane potentials (∆Ψm), which in turn trigger excessive ROS production. We propose that the ideal therapy should target the ETC non-invasively to prevent the generation of ROS from the onset of reflow. Accordingly, our overall goal in this application is to develop a new, non-invasive therapy to normalize mitochondrial hyperactivity during reflow. We will capitalize on the photoreceptive properties of cytochrome c oxidase (COX) for near infrared light (NIR) to modulate mitochondrial activity, thereby attenuating the production of ROS and, as a result, limit ischemia/reperfusion injury in the brain. Cytochrome c oxidase is the primary cellular photo- acceptor of NIR and the terminal enzyme of the ETC. We have discovered specific NIR wavelengths that partially inhibit COX (instead of activating COX, i.e., the current paradigm). We show that inhibitory NIR, applied at the time of reperfusion, provides profound neuroprotection. In this proposal, we will build on these compelling preliminary data and capitalize on the unique, multi-disciplinary expertise of our research team to: • Interrogate the molecular underpinnings of ischemia/reperfusion injury and of NIR therapy (Aim 1). • Uncover the mechanisms of NIR therapy following stroke (Aim 2) • Develop the optimal use of NIR therapy as a treatment for ischemic stroke (Aim 3).