TY - JOUR
T1 - Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke
AU - Monai, Hiromu
AU - Wang, Xiaowen
AU - Yahagi, Kazuko
AU - Lou, Nanhong
AU - Mestre, Humberto
AU - Xu, Qiwu
AU - Abe, Yoichiro
AU - Yasui, Masato
AU - Iwai, Youichi
AU - Nedergaard, Maiken
AU - Hirase, Hajime
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Drs. Shinichi Takahashi (Keio University), Elizabeth M. C. Hillman (Columbia University), K. C. Brennan (The University of Utah), Charles Yokoyama (RIKEN), and Paul Cumming for discussion and comments on the manuscript and the RIKEN Center for Brain Science–Olympus Collaboration Center for technical assistance with image acquisition. This work was supported by the RIKEN Center for Brain Science and Japan Society for the Promotion of Science KAKENHI Grants 18K14859 (to H. Monai), 26117520, 16H01888, and 18H05150 (to H.H.), 17K19637 and 16H05134 (to Y.A.), and 15H04688 and 18H02606 (to M.Y.). This work was also supported by Human Frontier Science Program Grant RGP0036/2014 (to H.H.); Japan Society for the Promotion of Science Core-to-Core Program Advanced Research Networks; the Adelson Medical Research Foundation (M.N.); the Lundbeck Foundation; the Novo Nordisk Foundation; and the US Department of Defense (M.N.). H.H. is a recipient of the Lundbeck Foundation Visiting Professorship.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/5/28
Y1 - 2019/5/28
N2 - Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K+ that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K+ homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K+, resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K+ clearance, representing a potent potential intervention for acute stroke.
AB - Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K+ that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K+ homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K+, resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K+ clearance, representing a potent potential intervention for acute stroke.
KW - AQP4
KW - Adrenergic receptor
KW - Aquaporin-4
KW - Extracellular potassium
KW - Ion
KW - Photothrombotic stroke
UR - http://www.scopus.com/inward/record.url?scp=85066238990&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066238990&partnerID=8YFLogxK
U2 - 10.1073/pnas.1817347116
DO - 10.1073/pnas.1817347116
M3 - Article
C2 - 31097598
AN - SCOPUS:85066238990
VL - 166
SP - 11010
EP - 11019
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 22
ER -