Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Stroke  

DOI： 10.5853/jos.2025.02607

Web of Science

Scopus

PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Communications Biology  

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.

DOI： 10.1038/s42003-022-03605-4

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Cerebral Blood Flow and Metabolism  

Post-stroke intra-infarct repair promotes peri-infarct neural reorganization leading to functional recovery. Herein, we examined the remodeling of extracellular matrix proteins (ECM) that constitute the intact basal membrane after permanent middle cerebral artery occlusion (pMCAO) in mice. Among ECM, collagen type IV remained localized on small vessel walls surrounding CD31-positive endothelial cells within infarct areas. Fibronectin was gradually deposited from peri-infarct areas to the ischemic core, in parallel with the accumulation of PDGFRβ-positive cells. Cultured PDGFRβ-positive pericytes produced fibronectin, which was enhanced by the treatment with PDGF-BB. Intra-infarct deposition of fibronectin was significantly attenuated in pericyte-deficient Pdgfrb^+/− mice. Phagocytic activity of macrophages against myelin debris was significantly enhanced on fibronectin-coated dishes. In contrast, laminin α2, produced by GFAP- and aquaporin 4-positive astrocytes, accumulated strongly in the boundary of peri-infarct areas. Pericyte-conditioned medium increased the expression of laminin α2 in cultured astrocytes, partly through TGFβ1. Laminin α2 increased the differentiation of oligodendrocyte precursor cells into oligodendrocytes and the expression of myelin-associated proteins. Peri-infarct deposition of laminin α2 was significantly reduced in Pdgfrb^+/− mice, with attenuated oligodendrogenesis in peri-infarct areas. Collectively, intra-infarct PDGFRβ-positive cells may orchestrate post-stroke remodeling of key ECM that create optimal environments promoting clearance of myelin debris and peri-infarct oligodendrogenesis.

DOI： 10.1177/0271678X221145092

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：GLIA  

NOX4 is a major reactive oxygen species-producing enzyme that modulates cell stress responses. We here examined the effect of Nox4 deletion on demyelination–remyelination, the most common pathological change in the brain. We used a model of cuprizone (CPZ)-associated demyelination–remyelination in wild-type and Nox4-deficient (Nox4^−/−) mice. While the CPZ-induced demyelination in the corpus callosum after 4 weeks of CPZ intoxication was slightly less pronounced in Nox4^−/− mice than that in wild-type mice, remyelination following CPZ withdrawal was significantly enhanced in Nox4^−/− mice with an increased accumulation of IBA1-positive microglia/macrophages in the demyelinating corpus callosum. Consistently, locomotor function, as assessed by the beam walking test, was significantly better during the remyelination phase in Nox4^−/− mice. Nox4 deletion did not affect autonomous growth of primary-culture oligodendrocyte precursor cells. Although Nox4 expression was higher in cultured macrophages than in microglia, Nox4^−/− microglia and macrophages both showed enhanced phagocytic capacity of myelin debris and produced increased amounts of trophic factors upon phagocytosis. The expression of trophic factors was higher, in parallel with the accumulation of IBA1-positive cells, in the corpus callosum in Nox4^−/− mice than that in wild-type mice. Nox4 deletion suppressed phagocytosis-induced increase in mitochondrial membrane potential, enhancing phagocytic capacity of macrophages. Treatment with culture medium of Nox4^−/− macrophages engulfing myelin debris, but not that of Nox4^−/− astrocytes, enhanced cell growth and expression of myelin-associated proteins in cultured oligodendrocyte precursor cells. Collectively, Nox4 deletion promoted remyelination after CPZ-induced demyelination by enhancing microglia/macrophage-mediated clearance of myelin debris and the production of trophic factors leading to oligodendrogenesis.

DOI： 10.1002/glia.24292

Web of Science

Scopus

PubMed

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：大道学館出版部  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Japanese Society of Neurological Therapeutics  

DOI： 10.15082/jsnt.42.6_s109

CiNii Research