Post-ischemic sodium glucose cotransporter inhibition attenuates ischemia–reperfusion injury via regulation of mitochondrial membrane potential

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.