Erdogan Mumin Alper, Yusuf Dimas, Christy Joanna, Solmaz Volkan, Erdogan Arife, Taskiran Emin, Erbas Oytun
Department of Physiology, Faculty of Medicine, Izmir Katip Celebi University, Izmir, Turkey.
Faculty of Medicine, University of Alberta, Edmonton, AB, Canada.
BMC Neurol. 2018 Jun 7;18(1):81. doi: 10.1186/s12883-018-1086-4.
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 < 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.
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.
在全球范围内，超过1000万人患有耐药性癫痫。需要新的治疗策略来应对这种使人衰弱的疾病。已证明抑制在大脑中差异表达的钠-葡萄糖协同转运蛋白（SGLT）可减少癫痫小鼠模型中的癫痫发作活动。在此，我们研究了目前用作糖尿病药物的高竞争性SGLT2抑制剂达格列净对戊四氮（PTZ）诱导癫痫发作的大鼠癫痫发作活动的影响。
将实验大鼠（n = 48）平均随机分为两个实验，每个实验有四个研究组：（1）输注生理盐水的载体处理（安慰剂）组；（2）输注PTZ的对照组；（3）PTZ和75 mg/kg达格列净的治疗组；（4）PTZ和150 mg/kg达格列净的另一个治疗组。通过脑电图以棘波百分比（SWP）测量评估研究对象的癫痫发作，或通过拉辛量表评分（RSS）和首次肌阵挛抽搐时间（TFMJ）进行临床评估。
用达格列净治疗的大鼠脑电图上的平均SWP较低（未治疗大鼠为20.4%，而未治疗大鼠为75.3%）。在行为上，用达格列净治疗改善了平均RSS（2.33对5.5）和平均TFMJ（68.3对196.7秒）。所有这些发现均具有统计学意义，p值<0.0001。使用150 mg/kg较高剂量的达格列净有更好地控制癫痫发作的趋势，然而这在统计学上并不始终具有显著意义。
达格列净降低了PTZ诱导癫痫发作大鼠的癫痫发作活动。这可能是由于葡萄糖可用性降低的抗癫痫作用以及跨神经元膜的钠转运减少，这可以赋予对兴奋性和不必要去极化的稳定作用。达格列净和其他SGLT2抑制剂作为抗癫痫药物的潜在临床作用应进一步探索。
