EXPRESS: Post-Ischemic Sodium Glucose Cotransporter Inhibition Attenuates Ischemia-Reperfusion Injury via Regulation of Mitochondrial Membrane Potential.

Authors

Tomoya Okamaoto, Hiromitsu Sasaki, Yudai Morisaki, Shohei Yokoyama, Yasuhiko Saito, Ichiro Nakagawa

Published in

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. Pages 271678X261468880. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

Ischemia-reperfusion injury remains a major clinical challenge even after successful recanalization in stroke patients. Mitochondrial membrane potential plays a key role in the neuroprotective effect against ischemia-reperfusion injury. While sodium-glucose cotransporter inhibitors exhibit pleiotropic organ-protective effects, their acute neuroprotective mechanisms against ischemia-reperfusion injury are not fully understood. We hypothesized that phlorizin, a sodium-glucose cotransporter inhibitor, provides neuroprotection through the maintenance of mitochondrial membrane potential.
We employed whole-cell patch-clamp and fluorometric imaging (Fura-2 and JC-1) in mouse hippocampal CA1 neurons to investigate the impact of phlorizin on synaptic activity, ion dynamics, and mitochondrial function during acute reperfusion in vitro.
Phlorizin (10 µM) significantly suppressed the post-reperfusion surge in spontaneous excitatory postsynaptic currents, N-methyl-D-aspartate receptor-mediated currents, and cytosolic Ca2+ concentration. Notably, JC-1 imaging revealed that phlorizin prevented abrupt mitochondrial repolarization, maintaining a relatively depolarized state. Consequently, phlorizin administration during reperfusion reduced CA1 neuronal death compared to controls.
Our findings demonstrate that acute sodium-glucose cotransporter inhibition exerts potent neuroprotection by modulating early ionic triggers and maintaining mitochondrial integrity. These results suggest that targeting neuronal sodium-glucose cotransporter may provide a novel therapeutic strategy to mitigate ischemia-reperfusion injury following acute ischemic stroke.

PMID:
42400131
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.

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