1097. Focused Ultrasound Combined with Intraarterial Mitochondria as Treatment Post-Ischemic Stroke

Authors: Pedro Norat; Catherine Gorick, BS; Michael Levitt, MD; Melanie Walker, MD; Min Park, MD; Petr Tvrdik, PhD; Richard Price, PhD; Yashar Kalani (Charlottesville, VA)

Mitochondria are the cell’s master regulators of energy and have been implicated in a diverse array of critical biological processes. Recently, mitochondria have been shown to transfer from astrocytes to neurons after ischemic stroke [1], possibly serving a neuroprotective role. Evidence supporting the transfer of mitochondria to ischemic tissue has been shown in experiments transplanting autologously derived mitochondria into infarcted heart tissue, which protected against ischemia-reperfusion injury [2]. Whether autologously derived mitochondria can be effectively delivered to infarcted brain tissue is unclear. Here we used a murine stroke model of transient middle cerebral artery occlusion (MCAO) to demonstrate that it is feasible to deliver viable mitochondria to regions of ischemic brain parenchyma. Mitochondria are initially isolated from the lateral gastrocnemius muscle. After undergoing 60 minutes of MCAO, we re-perfuse the stroke territory and immediately inject mitochondria into the ipsilateral internal carotid artery (ICA). We also combined this delivery method with concurrent Focused Ultrasound (FUS), which serves to disrupt the blood brain barrier. After four hours, the mice were sacrificed. We found that injected mitochondria were distributed into the stroked hemisphere, with an increase in the number of mitochondria delivered after using FUS. Furthermore, we were able to find mitochondrial uptake in neurons, astrocytes, and microglia. Cells that incorporated transplanted mitochondria were more likely to survive ischemic insult. These findings demonstrate that viable mitochondria transplantation intra-arterially is possible and may serve to stabilize neurons that pick up these mitochondria. Our results have implications for understanding the neuroprotective role of mitochondria after ischemic stroke and provide a new route and therapy after mechanical thrombectomy.