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Canagliflozin, an Inhibitor of the Na⁺-Coupled D-Glucose Cotransporter, SGLT2, Inhibits Astrocyte Swelling and Brain Swelling in Cerebral Ischemia

by Bosung Shim, Jesse A. Stokum, Mitchell Moyer, Natalya Tsymbalyuk, Orest Tsymbalyuk, Kaspar Keledjian, Svetlana Ivanova, Cigdem Tosun, Volodymyr Gerzanich and J. Marc Simard

Cells 2023, 12(18), 2221; https://doi.org/10.3390/cells12182221 - 6 Sep 2023

Cited by 10 | Viewed by 2812

Abstract

Brain swelling is a major cause of death and disability in ischemic stroke. Drugs of the gliflozin class, which target the Na⁺-coupled D-glucose cotransporter, SGLT2, are approved for type 2 diabetes mellitus (T2DM) and may be beneficial in other conditions, but data in cerebral ischemia are limited. We studied murine models of cerebral ischemia with middle cerebral artery occlusion/reperfusion (MCAo/R). Slc5a2/SGLT2 mRNA and protein were upregulated de novo in astrocytes. Live cell imaging of brain slices from mice following MCAo/R showed that astrocytes responded to modest increases in D-glucose by increasing intracellular Na⁺ and cell volume (cytotoxic edema), both of which were inhibited by the SGLT2 inhibitor, canagliflozin. The effect of canagliflozin was studied in three mouse models of stroke: non-diabetic and T2DM mice with a moderate ischemic insult (MCAo/R, 1/24 h) and non-diabetic mice with a severe ischemic insult (MCAo/R, 2/24 h). Canagliflozin reduced infarct volumes in models with moderate but not severe ischemic insults. However, canagliflozin significantly reduced hemispheric swelling and improved neurological function in all models tested. The ability of canagliflozin to reduce brain swelling regardless of an effect on infarct size has important translational implications, especially in large ischemic strokes. Full article

(This article belongs to the Section Cell and Gene Therapy)

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13 pages, 2347 KiB

Open AccessArticle

Trilobatin, a Novel SGLT1/2 Inhibitor, Selectively Induces the Proliferation of Human Hepatoblastoma Cells

by Lujing Wang, Min Liu, Fei Yin, Yuanqiang Wang, Xingan Li, Yucui Wu, Cuilian Ye and Jianhui Liu

Molecules 2019, 24(18), 3390; https://doi.org/10.3390/molecules24183390 - 18 Sep 2019

Cited by 29 | Viewed by 4538

Abstract

Studies have indicated that Na⁺-d-glucose co-transporter (SGLT) inhibitors had anti-proliferative activity by attenuating the uptake of glucose in several tumor cell lines. In this study, the molecular docking showed that, trilobatin, one of the dihydrochalcones from leaves of Lithocarpus polystachyus Rehd., might be a novel inhibitor of SGLT1 and SGLT2, which evidently attenuated the uptake of glucose in vitro and in vivo. To our surprise, we observed that trilobatin did not inhibit, but promoted the proliferation of human hepatoblastoma HepG2 and Huh 7 cells when it was present at high concentrations. At the same time, incubation with high concentrations of trilobatin arrested the cell cycle at S phase in HepG2 cells. We also found that treatment with trilobatin had no significant effect on the expression of hepatitis B x-interacting protein (HBXIP) and hepatocyte nuclear factor (HNF)-4α, the two key regulators of hepatocyte proliferation. Taken together, although trilobatin worked as a novel inhibitor of SGLTs to attenuate the uptake of glucose, it also selectively induced the cell proliferation of HepG2 cells, suggesting that not all the SGLT inhibitors inhibited the proliferation of tumor cells, and further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents. Full article

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