Eslami Seyyed Majid, Moradi Mohammad Mobin, Ghasemi Mehdi, Dehpour Ahmad Reza
Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Neurology, University of Massachusetts Medical Center, Worcester, MA, USA.
J Epilepsy Res. 2016 Dec 31;6(2):51-58. doi: 10.14581/jer.16011. eCollection 2016 Dec.
Status epilepticus (SE) is a neurological disorder with high prevalence and mortality rates, requiring immediate intervention. Licofelone is a cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitor, which its effectiveness to treat osteoarthritis has been approved. Increasing evidence suggests an involvement of COX and LOX enzymes in epileptic disorders. Thus, in the present study we investigate possible effects of licofelone on prevention and termination of SE. We also evaluated whether the nitrergic system could participate in this effect of licofelone.
We have utilized lithium-pilocarpine model of SE in adult Wistar rats to assess the potential effect of licofelone on seizure susceptibility. Licofelone was administered 1 h before pilocarpine. To evaluate probable role of nitric oxide (NO) system, L-arginine (60 mg/kg, i.p.), as a NO precursor; L-NAME (15 mg/kg, i.p.), as a non-selective nitric oxide synthase (NOS) inhibitor; aminoguanidine (100 mg/kg, i.p.), as an inducible NOS (iNOS) inhibitor and 7-nitroindazole (60 mg/kg, i.p.), as a neuronal NOS inhibitor were injected 15 min before licofelone. Also, licofelone and diazepam 10 mg/kg were administered 30 minutes after onset of SE.
Pre-treatment with licofelone at the dosage of 10 mg/kg, significantly prevented the onset of SE in all subjects ( < 0.001). L-arginine significantly inverted this anticonvulsant effect ( < 0.05). However, L-NAME and aminoguanidine, potentiated the anticonvulsant effect of licofelone ( < 0.05, < 0.01). Licofelone could not terminate seizures after onset which was terminated by diazepam.
Our findings showed that anticonvulsive effects of licofelone on SE could be mediated by iNOS. Also, we suggest that COX/5-LOX activation is possibly required in the initial stage of onset but SE recruits extra excitatory pathways with prolongation.
癫痫持续状态（SE）是一种患病率和死亡率都很高的神经系统疾病，需要立即进行干预。利考昔芬是一种环氧化酶（COX）和5-脂氧合酶（5-LOX）抑制剂，其治疗骨关节炎的有效性已获批准。越来越多的证据表明COX和LOX酶与癫痫疾病有关。因此，在本研究中，我们调查了利考昔芬对SE的预防和终止可能产生的影响。我们还评估了一氧化氮能系统是否参与利考昔芬的这一作用。
我们利用成年Wistar大鼠的锂-匹罗卡品SE模型来评估利考昔芬对癫痫易感性的潜在影响。在给予匹罗卡品前1小时给予利考昔芬。为了评估一氧化氮（NO）系统的可能作用，在给予利考昔芬前15分钟注射L-精氨酸（60mg/kg，腹腔注射）作为NO前体；L-硝基精氨酸甲酯（15mg/kg，腹腔注射）作为非选择性一氧化氮合酶（NOS）抑制剂；氨基胍（100mg/kg，腹腔注射）作为诱导型NOS（iNOS）抑制剂；7-硝基吲唑（60mg/kg，腹腔注射）作为神经元NOS抑制剂。此外，在SE发作30分钟后给予利考昔芬和10mg/kg地西泮。
以10mg/kg的剂量预处理利考昔芬可显著预防所有受试动物的SE发作（<0.001）。L-精氨酸显著逆转了这种抗惊厥作用（<0.05）。然而，L-硝基精氨酸甲酯和氨基胍增强了利考昔芬的抗惊厥作用（<0.05，<0.01）。利考昔芬不能在发作后终止癫痫发作，而地西泮可终止发作。
我们的研究结果表明，利考昔芬对SE的抗惊厥作用可能由iNOS介导。此外，我们认为在发作的初始阶段可能需要COX/5-LOX激活，但随着SE的延长会募集额外的兴奋性通路。
