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

被引:58
作者
Erdogan, Mumin Alper [1 ]
Yusuf, Dimas [2 ]
Christy, Joanna [3 ]
Solmaz, Volkan [4 ]
Erdogan, Arife [5 ]
Taskiran, Emin [6 ]
Erbas, Oytun [7 ]
机构
[1] Izmir Katip Celebi Univ, Fac Med, Dept Physiol, Izmir, Turkey
[2] Univ Alberta, Fac Med, Edmonton, AB, Canada
[3] Simon Fraser Univ, Burnaby, BC, Canada
[4] Trakya Univ, Dept Neurol, Fac Med, Edirne, Turkey
[5] Izmir Bozyaka Training & Res Hosp, Dept Emergency Med, Izmir, Turkey
[6] Tepecik Training & Res Hosp, Dept Internal Med, Izmir, Turkey
[7] Bilim Univ, Dept Physiol, Fac Med, Istanbul, Turkey
关键词
Dapagliflozin; Epilepsy; Pentylenetetrazol; Sodium-glucose linked transporter; SODIUM-GLUCOSE TRANSPORTER; RAT-BRAIN; FUNCTIONAL EXPRESSION; ISCHEMIA; COTRANSPORTERS; DAMAGE; SLEEP;
D O I
10.1186/s12883-018-1086-4
中图分类号
R74 [神经病学与精神病学];
学科分类号
100204 [神经病学];
摘要
Background: 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. Methods: 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). Results: 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 < 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. Conclusions: Dapagliflozin 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.
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页数:8
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