Sodium-glucose cotransporter 2 inhibitor partially improves brain mitochondrial function, but does not mitigate...

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are recommended to treat heart failure (HF) with the benefit of mitigating cognitive impairment in HF patients with type 2 diabetes. However, the underlying mechanisms are still unclear. This study aimed to investigate whether SGLT2i can improve cognitive function and synaptic plasticity in rats with myocardial infarction (MI) through attenuating inflammation, oxidative stress, impaired metabolism, and mitochondrial dysfunction in the brain. Male rats (n = 8/group) underwent either a sham operation or MI induced by permanent ligation of the left anterior descending coronary artery. MI rats with ejection fraction <50 % were divided into three groups to receive either a vehicle, SGLT2i (Dapagliflozin, 1 mg/kg), or angiotensin-converting enzyme inhibitor (Enalapril, 10 mg/kg, positive control) for four weeks. Cardiac function, cognitive function, synaptic plasticity, dendritic spine density, and brain biochemical changes were assessed at the end of the protocol. MI rats exhibited cardiac dysfunction, hippocampal-dependent cognitive impairment, impaired synaptic plasticity, and loss of dendritic spines. Brain oxidative stress, inflammation, and mitochondrial dysfunction were also observed in MI rats. Treatment with SGLT2i and ACEi improved cardiac function but failed to attenuate cognitive impairment, synaptic dysplasticity, and loss of dendritic spine density in MI rats. A decrease in brain glutamate level was found following MI, which can be restored by SGLT2i and ACEi. Only SGLT2i partially improved brain mitochondrial function. In summary, SGLT2i enhanced glutamate levels and partially improved mitochondrial function in the brain; however, these changes were insufficient to improve cognitive function in MI rats.