TY - JOUR
T1 - Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects
AU - Takashima, Masamitsu
AU - Nakamura, Kuniyuki
AU - Kiyohara, Takuya
AU - Wakisaka, Yoshinobu
AU - Hidaka, Masaoki
AU - Takaki, Hayato
AU - Yamanaka, Kei
AU - Shibahara, Tomoya
AU - Wakisaka, Masanori
AU - Ago, Tetsuro
AU - Kitazono, Takanari
N1 - Funding Information:
We would like to thank Naoko Kasahara (Kyushu University) for providing technical support and Keiko Hirano (Kyushu University) for providing secretarial assistance. We appreciate the technical assistance from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. We would also like to thank Editage (www.editage.com) for English language editing. This study was supported in part by Grants-in-Aid for Scientific Research (B 16H05439 and B 20H03791 to T. Kitazono and T.A.; C 20K09373 to T.A.; C 26462163, C 19K09530, and C 22K09209 to Y.W.; C 19K09511 and C 22K09236 to K.N.) and Grant-in-Aid for Research Activity Start-up (21K20693 to T.S.) from the Japan Society for the Promotion of Science (JSPS); a grant from Mochida Memorial Foundation for Medical and Pharmaceutical Research (K.N.); a grant from SENSHIN Medical Research Foundation, Japan (K.N., T.S., and T.A.); a grant from the Smoking Research Foundation (T.A.); and research grants from Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, MSD, Sanofi, and Takeda (T. Kitazono and T.A.). This work was also supported by a research fund from Taisho Pharmaceutical Co., Ltd (Tokyo, Japan). The funders had no role in the study design, data collection, data analysis, or preparation of the manuscript. Luseogliflozin was obtained from Taisho Pharmaceutical Co., Ltd.
Funding Information:
We would like to thank Naoko Kasahara (Kyushu University) for providing technical support and Keiko Hirano (Kyushu University) for providing secretarial assistance. We appreciate the technical assistance from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. We would also like to thank Editage ( www.editage.com ) for English language editing. This study was supported in part by Grants-in-Aid for Scientific Research (B 16H05439 and B 20H03791 to T. Kitazono and T.A.; C 20K09373 to T.A.; C 26462163, C 19K09530, and C 22K09209 to Y.W.; C 19K09511 and C 22K09236 to K.N.) and Grant-in-Aid for Research Activity Start-up (21K20693 to T.S.) from the Japan Society for the Promotion of Science (JSPS); a grant from Mochida Memorial Foundation for Medical and Pharmaceutical Research (K.N.); a grant from SENSHIN Medical Research Foundation, Japan (K.N., T.S., and T.A.); a grant from the Smoking Research Foundation (T.A.); and research grants from Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, MSD, Sanofi, and Takeda (T. Kitazono and T.A.). This work was also supported by a research fund from Taisho Pharmaceutical Co., Ltd (Tokyo, Japan). The funders had no role in the study design, data collection, data analysis, or preparation of the manuscript. Luseogliflozin was obtained from Taisho Pharmaceutical Co., Ltd.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury.
AB - Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury.
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UR - http://www.scopus.com/inward/citedby.url?scp=85133327226&partnerID=8YFLogxK
U2 - 10.1038/s42003-022-03605-4
DO - 10.1038/s42003-022-03605-4
M3 - Article
C2 - 35780235
AN - SCOPUS:85133327226
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 653
ER -
