Access Type

Open Access Dissertation

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Physiology

First Advisor

Thomas H. Sanderson

Second Advisor

Maik Huttemann

Abstract

Acute ischemic stroke is a debilitating disease that causes significant brain injury.

While rapid restoration of blood flow is critical to salvage the ischemic brain, reperfusion

of tissue can further drive brain damage by inducing generation of mitochondrial reactive

oxygen species (Chouchani et al., 2014a). Recent studies by our group found that noninvasive

mitochondrial modulation (NIMM) with near-infrared (NIR) light can limit the

production of reactive oxygen species following global brain ischemia (T. H. Sanderson

et al., 2018). NIR interacts with the rate limiting step of the mitochondrial electron

transport chain (ETC), cytochrome c oxidase (COX), and modulates mitochondrial

respiration. Under conditions of mitochondrial stress, such as reperfusion following

ischemia, specific wavelengths of NIR can limit the production of ROS by transiently

reducing COX activity, and thus limiting a critical force for ROS production, stress-induced

mitochondrial membrane potential hyperpolarization. Here, we evaluated a specific

combination of COX-inhibitory NIR (750nm and 950nm) as a potential therapy for acute

ischemic stroke using a rat MCAO model. We found the NIMM at the onset of reperfusion

resulted in a 20% reduction of infarct volume measured 24 hours post reperfusion. This

reduction in infarct was sustained through the chronic phase of stroke and the

neuroprotective benefit increased to 50% infarct reduction when treatment duration was

douple to 240 minutes. Our data suggest that NIMM by targeting COX with NIR irradiation

at the onset of reperfusion can be a beneficial therapy to minimize reperfusion injury

following acute ischemic stroke and that extending the treatment window beyond the

initial ROS burst can target other long-term causes of neuronal death following stroke

such as inflammation.

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