目的:κ阿片受体(KOR)激动剂具有抗惊厥作用,但其抗癫痫作用尚不清楚。U50488是一种选择性KOR激动剂,用于确定其对癫痫持续状态(SE)的影响。大鼠锂-毛果芸香碱SE模型的自发性惊厥性癫痫(SS)和认知障碍。还研究了抗癫痫药物左乙拉西坦的作用。
方法:雄性Wistar大鼠分为三组,即LiP,LiP+U50488(10mg/kg,i.p.)和LiP+左乙拉西坦(400毫克/千克,i.p.)组。使用地西泮(15mg/kg,i.p.)和苯巴比妥(25mg/kg,i.p.)。在SE发作15分钟后开始药物治疗,并在4小时后重复一次。每天12小时(上午9点至下午9点)对大鼠进行视频监测,以使用第0天至第21天的改良Racine量表和SS的发作和频率来确定SE的严重程度。在基线即第-1天(锂施用前)和第22天进行Morris水迷宫(MWM)测试,以评估认知障碍。
结果:与LiP相比,U50488降低了SE的严重程度(1.98±0.13vs2.95±0.12;p值<0.0001),但未降低左乙拉西坦(2.62±0.09;p值=0.3112)。两者的存活率都增加了U50488(90%,n=10)和左乙拉西坦(81.8%,n=11)与NS(56.2%,n=16)。U50488/左乙拉西坦对SS的发作和频率无影响。U50488改善癫痫发作引起的认知障碍。左乙拉西坦组在9只大鼠中的8只在MWM中显示出thigmotiactic(壁拥抱)行为。
结论:使用κ阿片受体激动剂U50488急性治疗对SE有有益作用,SE相关死亡率和记忆障碍。U50488对癫痫发作和相关认知损害的双重保护作用优于目前使用的已知引起认知损害的抗癫痫发作药物。
Kappa opioid receptor (KOR) agonists have anticonvulsant effect but their antiepileptogenic effect is unknown. U50488, a selective KOR agonist is used to determine its effect on status epilepticus (SE), spontaneous convulsive seizures (SS) and cognitive impairment in rat lithium-pilocarpine SE model. Effect of an antiepileptic drug levetiracetam is also studied.
Male Wistar rats with SE were divided into three groups namely, LiP, LiP + U50488 (10 mg/kg, i.p.) and LiP + levetiracetam (400 mg/kg, i.p.) group. SE was terminated after 90 min of its onset with diazepam (15 mg/kg, i.p.) and phenobarbitone (25 mg/kg, i.p.). Drug treatment was started after 15 min of onset of SE and repeated once after 4 h. Rats were video monitored 12 h daily (9 AM to 9 PM) to determine severity of SE using modified Racine scale and onset and frequency of SS from day 0 to day 21. Morris water maze (MWM) test was done at baseline i.e. day -1 (before lithium administration) and day 22, to assess cognitive impairment.
As compared to LiP, U50488 decreased the severity of SE (1.98 ± 0.13 vs 2.95 ± 0.12; p-value < 0.0001) but not levetiracetam (2.62 ± 0.09; p-value = 0.3112). Survival increased with both U50488 (90%, n = 10) and levetiracetam (81.8%, n = 11) as compared to NS (56.2%, n = 16). No effect on onset and frequency of SS was found in U50488/levetiracetam group. U50488 improved seizures-induced cognitive impairment. Levetiracetam group showed thigmotactic (wall hugging) behaviour in MWM in 8 out of 9 rats.
Acute treatment with U50488, a kappa opioid receptor agonist has a beneficial effect on SE, SE-related mortality and memory impairment. The dual protective effect of U50488 on seizures and related cognitive impairment is advantageous over currently used antiseizure drugs which are known to cause cognitive impairment.