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

• Published in: Molecular neurobiology 2010-06, Vol.41 (2-3), p.172-179
• Main Authors: Jung, Joo Eun, Kim, Gab Seok, Chen, Hai, Maier, Carolina M, Narasimhan, Purnima, Song, Yun Seon, Niizuma, Kuniyasu, Katsu, Masataka, Okami, Nobuya, Yoshioka, Hideyuki, Sakata, Hiroyuki, Goeders, Christina E, Chan, Pak H
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cerebral ischemia; CK2; Disease Models, Animal; Hemorrhage; Humans; Mice; Mice, Knockout; mitochondria; Mn-SOD; Molecular biology; NADPH oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Neurobiology; Neurology; Neuroprotective Agents - therapeutic use; Neuroprotective signaling; Neurosciences; Oxidative Stress; reactive oxygen species; Reperfusion Injury - complications; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Reperfusion Injury - therapy; Rodents; Signal Transduction - physiology; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stroke; Stroke - complications; Stroke - pathology; Stroke - physiopathology; Stroke - therapy; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-010-8102-z

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.