Inhibition of sodium-glucose cotransporter 2 prevents sorafenib-induced depression-like behaviors by preserving hippocampal-dependent long-term potentiation.

The sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin has been reported to exert significant neuroprotective effects on neurobehavioral deficits; however, its effects on chemotherapy-induced neuroplastic changes have not yet been investigated. The present study investigates the behavioral changes and hippocampal cellular responses through which empagliflozin exerts antidepressant effects against chemotherapy-induced pathological alterations. We employed a mouse model of depression induced by oral administration of the chemotherapeutic agent sorafenib for 28 days. Sorafenib-induced cardiotoxicity was assessed using immunohistochemistry. Behavioral changes were evaluated using the forced swim test (FST), tail suspension test (TST), sucrose preference test (SPT), female urine sniffing test (FUST), and open field test (OFT). Synaptic transmission and long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses were measured using extracellular field recordings. Oral administration of sorafenib induced macrophage infiltration and apoptosis in mouse hearts, whereas co-treatment with empagliflozin prevented these effects. In addition to cardiotoxicity, sorafenib also elicited depression-like behaviors, as evidenced by increased immobility time in the FST and TST, reduced sucrose preference in the SPT, decreased sniffing time in the FUST, and reduced time spent in the central zone during the OFT. Moreover, these neurological impairments were accompanied by a reduced input-output curve and diminished magnitude of LTP at hippocampal Schaffer collateral-CA1 synapses. Co-treatment with empagliflozin effectively prevented these neurological and cellular changes. Inhibition of sodium-glucose cotransporter-2 prevents sorafenib-induced depression-like behaviors and suppresses the decline in synaptic transmission and LTP in the hippocampus, thereby contributing to the antidepressant effects of empagliflozin.