Anticonvulsive Effects of Licofelone on Status Epilepticus Induced by Lithium-pilocarpine in Wistar Rats: a Role for Inducible Nitric Oxide Synthase

Abstract

Background and PurposeStatus 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.MethodsWe 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.ResultsPre-treatment with licofelone at the dosage of 10 mg/kg, significantly prevented the onset of SE in all subjects (p < 0.001). L-arginine significantly inverted this anticonvulsant effect (p < 0.05). However, L-NAME and aminoguanidine, potentiated the anticonvulsant effect of licofelone (p < 0.05, p < 0.01). Licofelone could not terminate seizures after onset which was terminated by diazepam.ConclusionsOur 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.

Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide

“…Pre-treatment with 7-NI did not change seizure susceptibility significantly, but coadministration of AG and licofelone exerted anticonvulsive effects. These data suggested that the NO pathway especially iNOS contributes to the anticonvulsive effects of licofelone (52). (Fig.…”

Seizure-Induced Oxidative Stress in Status Epilepticus: Is Antioxidant Beneficial?

“…The inflammatory response following status epilepticus causes activation of inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) reacts with O 2 - to form the peroxynitrite and contributes the severity of oxidative stress in kainic-acid induced experimental status epilepticus in our previous studies [ 25 , 26 , 27 , 28 ]. Several studies with a various animal model of status epilepticus such as pilocarpine-induced, pentylenetetrazole-induced, diisopropylfluorophosphate, lithium-pilocarpine model, also demonstrated the critical role of NO-related pathway and neuro-inflammation contributing to neuronal damage [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Sumatriptan reduces severity of status epilepticus induced by lithium–pilocarpine through nitrergic transmission and 5‐HT1B/D receptors in rats: A pharmacological‐based evidence

“…Pilocarpine, lithium chloride, sumatriptan, GR‐127935, scopolamine methyl bromide, L‐NAME, 7‐nitroindazole, aminoguanidine, ketamine, and xylazine were injected intraperitoneally (i.p.). The doses of drugs, route of administration, and the time of injection were selected based on previous experiments, our pilot studies, and pharmacokinetic consideration [20,23,27,31].…”

“…Nitric oxide (NO) is produced from the amino acid L‐arginine through activity of different isoforms of NO synthase (NOS) enzymes including endothelial NO (eNOS), inducible (iNOS), and neuronal (nNOS). There is ample evidence that NO plays a role in different types of seizure such as SE [26,27]. At the early stages of SE, nNOS is responsible for NO overproduction; and iNOS intervenes in continuous excess NO generation for a long time, resulting in neuronal cell death in rodents [28].…”