Abstract
BackgroundWorldwide, 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.MethodsLaboratory 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).ResultsRats 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 < 0.0001. There was a trend towards even better seizure control with the higher dose of dapagliflozin at 150 mg/kg, however this was not consistently statistically significant.ConclusionsDapagliflozin decreased seizure activity in rats with PTZ–induced seizures. This may be explained by the anti-seizure effects of decreased glucose availability and a reduction in sodium transport across neuronal membranes which can confer a stabilizing effect against excitability and unwanted depolarization. The potential clinical role of dapagliflozin and other SGLT2 inhibitors as anti-seizure medications should be further explored.
Highlights
Worldwide, over 10 million individuals suffer from drug-resistant epilepsy
Dapagliflozin, a potent sodium-glucose cotransporter 2 (SGLT2) inhibitor used for diabetes, may have anti-seizure effects
While glucose transporter 1 (GLUT1) is the predominant isoform expressed in the blood-brain barrier (BBB) and glial cells [18], glucose transporter 3 (GLUT3) is the dominant isoform expressed in neurons [19]
Summary
Over 10 million individuals suffer from drug-resistant epilepsy. New therapeutic strategies are needed to address this debilitating disease. Epidemiology of drug-resistant epilepsy Worldwide, over 50 million people live with epilepsy, and about 10 million develop drug-resistant epilepsy, an often-debilitating disease. Despite ongoing developments in the diagnosis and management of epilepsy, about 20 to 30% of patients have epilepsy that is resistant to treatment, which is often called drug-resistant epilepsy. Used antiepileptic drugs (AEDs) can have pronounced side effect profiles, low tolerability, and narrow therapeutic ranges. Patients who require multiple AEDs to control their epilepsy often experience adverse effects that can range from somnolence, headaches, blunting of cognition, to more serious reactions that include mood changes, arrhythmias, and interference with the functioning of other drugs. Despite numerous studies to advance the treatment of epilepsy, the ideal treatment remains elusive for many patients who live with refractory disease [2]
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