Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol-induced murine model of epilepsy

摘要

Worldwide, over 10 million individuals suffer from drug-resistant epilepsy. New therapeutic strategies are needed to address this debilitating disease. Inhibition of sodium-glucose linked transporters (SGLTs), which are variably expressed in the brain, has been demonstrated to reduce seizure activity in murine models of epilepsy. Here we investigated the effects of dapagliflozin, a highly competitive SGLT2 inhibitor currently used as a drug for diabetes mellitus, on seizure activity in rats with pentylenetetrazol (PTZ) induced seizures. Laboratory rats (n?=?48) were evenly randomized into two experiments, each with four study arms: (1) a vehicle-treated (placebo) arm infused with saline; (2) a control arm infused with PTZ; (3) a treatment arm with PTZ and dapagliflozin at 75?mg/kg, and (4) another treatment arm with PTZ and dapagliflozin at 150?mg/kg. Study subjects were assessed for seizures either via EEG as measured by spike wave percentage (SWP), or clinically via Racine’s scales scores (RSS) and time to first myoclonic jerk (TFMJ). Rats treated with dapagliflozin had lower mean SWP on EEG (20.4% versus 75.3% for untreated rats). Behaviorally, treatment with dapagliflozin improved means RSS (2.33 versus 5.5) and mean TFMJ (68.3 versus 196.7?s). All of these findings were statistically significant with p-values of