Hisayuki Hosoo1, Aiki Marushima2, Yukio Nagasaki1, Aki Hirayama1, Hiromu Ito1, Sandra Puentes1, Arnela Mujagic1, Hideo Tsurushima1, Wataro Tsuruta1, Kensuke Suzuki1, Hirofumi Matsui1, Yuji Matsumaru1, Tetsuya Yamamoto1, Akira Matsumura1. 1. From the Department of Neurosurgery, Faculty of Medicine (H.H., A.M., H.T., W.T., Y.M., T.Y., A.M.), Department of Neurosurgery, Graduate School of Comprehensive Human Science (H.H., A. Marushima, A. Mujagic, H.T., W.T., Y.M., T.Y., A.M.), Graduate School of Pure and Applied Sciences (Y.N.), Department of Gastroenterology, Graduate School of Comprehensive Human Science (H.I., H.M.), and Graduate School of Systems and Information Engineering (S.P.), University of Tsukuba, Ibaraki, Japan; Center for Integrative Medicine, Tsukuba University of Technology, Ibaraki, Japan (A.H.); and Department of Neurosurgery, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan (K.S.). 2. From the Department of Neurosurgery, Faculty of Medicine (H.H., A.M., H.T., W.T., Y.M., T.Y., A.M.), Department of Neurosurgery, Graduate School of Comprehensive Human Science (H.H., A. Marushima, A. Mujagic, H.T., W.T., Y.M., T.Y., A.M.), Graduate School of Pure and Applied Sciences (Y.N.), Department of Gastroenterology, Graduate School of Comprehensive Human Science (H.I., H.M.), and Graduate School of Systems and Information Engineering (S.P.), University of Tsukuba, Ibaraki, Japan; Center for Integrative Medicine, Tsukuba University of Technology, Ibaraki, Japan (A.H.); and Department of Neurosurgery, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan (K.S.). aiki.marushima@md.tsukuba.ac.jp.
Abstract
BACKGROUND AND PURPOSE: Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke. However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia-reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection. METHODS: C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radical-scavenging capacities were analyzed by an electron paramagnetic resonance-based method. RESULTS: RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O2- production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O2- improved by RNP treatment. CONCLUSIONS: An intra-arterial RNP injection after cerebral ischemia-reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection.
BACKGROUND AND PURPOSE: Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke. However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia-reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection. METHODS: C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radical-scavenging capacities were analyzed by an electron paramagnetic resonance-based method. RESULTS: RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O2- production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O2- improved by RNP treatment. CONCLUSIONS: An intra-arterial RNP injection after cerebral ischemia-reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection.
Authors: Graeme A Deuchar; Josie C van Kralingen; Lorraine M Work; Celestine Santosh; Keith W Muir; Chris McCabe; I Mhairi Macrae Journal: Transl Stroke Res Date: 2018-11-30 Impact factor: 6.829