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Reperfusion and Neurovascular Dysfunction in Stroke: from Basic Mechanisms to Potential Strategies for Neuroprotection

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Abstract

Effective stroke therapies require recanalization of occluded cerebral blood vessels. However, reperfusion can cause neurovascular injury, leading to cerebral edema, brain hemorrhage, and neuronal death by apoptosis/necrosis. These complications, which result from excess production of reactive oxygen species in mitochondria, significantly limit the benefits of stroke therapies. We have developed a focal stroke model using mice deficient in mitochondrial manganese-superoxide dismutase (SOD2−/+) to investigate neurovascular endothelial damage that occurs during reperfusion. Following focal stroke and reperfusion, SOD2−/+ mice had delayed blood-brain barrier breakdown, associated with activation of matrix metalloproteinase and high brain hemorrhage rates, whereas a decrease in apoptosis and hemorrhage was observed in SOD2 overexpressors. Thus, induction and activation of SOD2 is a novel strategy for neurovascular protection after ischemia/reperfusion. Our recent study identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse SOD2 gene. During reperfusion, activation of STAT3 and its recruitment into the SOD2 gene were blocked, resulting in increased oxidative stress and neuronal apoptosis. In contrast, pharmacological activation of STAT3 induced SOD2 expression, which limits ischemic neuronal death. Our studies point to antioxidant-based neurovascular protective strategies as potential treatments to expand the therapeutic window of currently approved therapies.

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Acknowledgments

This work was supported by grants P50 NS014543, RO1 NS025372, RO1 NS036147, and RO1 NS038653 from the National Institutes of Health and by the James R. Doty Endowment. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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  1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305-5487, USA

    Joo Eun Jung, Gab Seok Kim, Hai Chen, Carolina M. Maier, Purnima Narasimhan, Yun Seon Song, Kuniyasu Niizuma, Masataka Katsu, Nobuya Okami, Hideyuki Yoshioka, Hiroyuki Sakata, Christina E. Goeders & Pak H. Chan

  2. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305-5487, USA

    Joo Eun Jung, Gab Seok Kim, Hai Chen, Carolina M. Maier, Purnima Narasimhan, Yun Seon Song, Kuniyasu Niizuma, Masataka Katsu, Nobuya Okami, Hideyuki Yoshioka, Hiroyuki Sakata, Christina E. Goeders & Pak H. Chan

  3. Program in Neurosciences, Stanford University School of Medicine, Stanford, CA, 94305-5487, USA

    Joo Eun Jung, Gab Seok Kim, Hai Chen, Carolina M. Maier, Purnima Narasimhan, Yun Seon Song, Kuniyasu Niizuma, Masataka Katsu, Nobuya Okami, Hideyuki Yoshioka, Hiroyuki Sakata, Christina E. Goeders & Pak H. Chan

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  1. Joo Eun Jung
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Jung, J.E., Kim, G.S., Chen, H. et al. Reperfusion and Neurovascular Dysfunction in Stroke: from Basic Mechanisms to Potential Strategies for Neuroprotection. Mol Neurobiol 41, 172–179 (2010). https://doi.org/10.1007/s12035-010-8102-z

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