Empagliflozin attenuates PTZ-induced neurotoxicity and enhances the protective effects of levetiracetam: Associations with NRF2/GPX4 and AMPK/ULK1/ LC3-II signaling
Abstract
Purpose: To investigate the antiseizure and neuroprotective effects of empagliflozin (EMPA), administered alone or in combination with levetiracetam (LEV), in pentylenetetrazole (PTZ)-induced epilepsy model in rats.
Methods: A modified window-PTZ kindling model was used to investigate associated biochemical and molecular changes. Rats were assigned to six groups: control, PTZ, LEV (200 mg/kg), EMPA (3 mg/kg), EMPA (10 mg/kg) and EMPA (10 mg/kg) plus LEV (100 mg/kg) groups. Seizure severity, open-field behavior, hippocampal histopathology, oxidative stress markers, sodium-glucose cotransporter-2 (SGLT2) and gamma-aminobutyric acid (GABA) levels, nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4) levels, unc-51-like kinase 1 (ULK1) and microtubule-associated protein 1 light chain 3-II (LC3-II) levels, and adenosine monophosphate-activated protein kinase (AMPK) activation were evaluated.
Results: EMPA reduced PTZ-induced seizure severity in a dose-related manner, with the higher dose producing greater suppression of seizure severity, improved locomotor and exploratory behavior, and attenuated hippocampal histopathological alterations. It also attenuated oxidative damage, improved antioxidant capacity, increased GABA levels, and reduced hippocampal SGLT2 expression. In addition, EMPA modulated NRF2 and GPX4 levels and was associated with changes in autophagy-related signaling, including increased AMPK activation and higher ULK1 and LC3-II…
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