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- Title
Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects.
- Authors
Takashima, Masamitsu; Nakamura, Kuniyuki; Kiyohara, Takuya; Wakisaka, Yoshinobu; Hidaka, Masaoki; Takaki, Hayato; Yamanaka, Kei; Shibahara, Tomoya; Wakisaka, Masanori; Ago, Tetsuro; Kitazono, Takanari
- Abstract
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. Pre-treatment of non-diabetic mice with the SGLT2 inhibitor, luseogliflozin, reduces brain damage and neurological dysfunction following middle cerebral artery occlusion by acquiring ischemic tolerance in pericytes.
- Subjects
SODIUM-glucose cotransporter 2 inhibitors; BRAIN injuries; ISCHEMIC stroke; BRAIN damage; ARTERIAL occlusions; SODIUM-glucose cotransporters; PROTEIN kinases
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03605-4