Pharmacological inhibition of inducible nitric oxide synthase attenuates the development of seizures in mice

Rehni, Ashish K.; Singh, Thakur Gurjeet; Kalra, Rohit; Singh, Nirmal

doi:10.1016/j.niox.2009.06.001

Cited by 31 publications

(12 citation statements)

References 19 publications

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“…This pretreatment increased the latency to the first seizure and latency to death. These effects were also found in the study of Rehni et al [15], who showed a similar protective effect of aminoguanidine using pentylenetetrazole-induced kindled seizures and pilocarpine-induced status epilepticus in mice. When using a highly specific iNOS inhibitor, 1400W, we did not observe any changes in the behavioural parameters analysed.…”

Section: Discussionsupporting

confidence: 80%

“…Earlier studies on NO have suggested that it has an anticonvulsant effect [12,16], and newer studies have shown an association with proconvulsant effects [14,15]. This apparent contradiction can be explained by the different experimental conditions (animal species, type of seizures and inducing agent), including the pharmacological tools used to modify the NO pathway [16].…”

Section: Discussionmentioning

confidence: 99%

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Involvement of the Nitric Oxide/Cyclic Guanylate Monophosphate Pathway in the Pilocarpine-Induced Seizure Model in Mice

Rios

Rocha²,

Carvalho³

et al. 2013

Pharmacology

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The present study was designed to investigate the involvement of the nitric oxide (NO)/cyclic guanylate monophosphate pathway in pilocarpine-induced seizures in mice. Male Swiss mice (26–32 g) were used as the in vivo model. The following pharmacological tools were utilized: the non-selective NO synthase (NOS) inhibitor L-NAME (10 mg/kg, i.p.), a preferential inducible NOS (iNOS) inhibitor aminoguanidine (25 mg/kg, i.p.), a highly specific iNOS inhibitor 1400W (2.5 mg/kg, i.p.), the NO donor L-arginine (150 mg/kg, i.p.), and the soluble guanylyl cyclase inhibitor ODQ (10 mg/kg, i.p.). The animals were divided into groups (n = 8) and pretreated for 30 min before receiving pilocarpine (400 mg/kg, i.p.), while the control group received only pilocarpine. They were observed for 60 min to measure initial seizure latency, latency till death, and mortality. An administration of L-NAME or ODQ delayed the onset of initial seizure, increased latency till death, and produced a 25% survival rate. Aminoguanidine increased the initial seizure and latency until death, and administration of 1400W did not have an effect. Incremental increases of NO by L-arginine were capable of decreasing the seizure and death latency. These results support the idea that the constitutive NOS, probably neuronal NOS, followed by soluble guanylyl cyclase activation is involved in the convulsive responses caused by pilocarpine administration.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Involvement of the Nitric Oxide/Cyclic Guanylate Monophosphate Pathway in the Pilocarpine-Induced Seizure Model in Mice

Rios

Rocha²,

Carvalho³

et al. 2013

Pharmacology

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“…Down regulation of iNOS was found to attenuate the progress of chemically induced seizures and neuronal damage [56,57]. PTZ-induced seizures, increased iNOS activity in hippocampus [57].…”

Section: Discussionmentioning

confidence: 95%

“…Considering the fact that higher activity of nNOS and iNOS are associated with excitotoxicity, NO formation is amplified through epileptic seizures [57]. Expression of iNOS in brain stimulates glutamatergic pathway and causes hyperexcitability [56]. Interestingly, there is strong evidence about resistance to formation of PTZ kindling in the iNOS knockout mice [58].…”

Section: Discussionmentioning

confidence: 99%

A COX/5-LOX Inhibitor Licofelone Revealed Anticonvulsant Properties Through iNOS Diminution in Mice

et al. 2015

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Licofelone is a COX/5-LOX inhibitor, which recently was approved as an effective treatment for osteoarthritis. Beside its analgesic and anti-inflammatory effects, some reports show neuro-protective properties for this agent in central nervous system. Several lines of evidence declare the involvement of COX or LOX isoenzymes in epileptic disorders. To set the foundation for future research into the neurobiology of licofelone as a potential therapeutic agent, we studied the effect of licofelone in an animal model of epilepsy. Although different neurotransmitters and neuro-modulators like nitric oxide were introduced as suggested targets of licofelone, the underlying mechanisms of central effects of this drug are not still fully understood. We have utilized pentylenetetrazole-induced clonic seizure model to investigate the behavioral consequences of licofelone administration and its possible mechanisms in seizure susceptibility. Licofelone revealed anticonvulsant properties at the dose of 10 mg/kg (i.p) or higher in mice. Pre-treatment with NO (nitric oxide) donor, L-arginine, reversed this anticonvulsant effects dose dependently. L-NAME, as a non-selective nitric oxide synthase (NOS) inhibitor, potentiated the anticonvulsant effects of licofelone. A neuronal NOS inhibitor, 7-NI did not affect seizure threshold alone or in combination with licofelone. Using non-effective doses of selective inhibitors of inducible NOS, aminoguanidine or 1400W, significantly increased the seizure threshold when were accompanied by licofelone in low doses. These data support the involvement of NO as an important role player in the central neuro-protective properties of licofelone. Furthermore, it implies that down regulation of iNOS seems crucial for anticonvulsant properties of this COX/5-LOX inhibitor in seizure susceptibility.

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“…Increment of hippocampal nitrite content after SE, suggests a role for NO system in SE 51. Glutamate release due to NOS activation might be the underlying mechanism 52. In one study, median convulsive dose of ciprofloxacin was increased by AG and decreased with L-arginine, suggesting that elevation of brain glutamate is the consequence of iNOS activation 53.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Pharmacological inhibition of inducible nitric oxide synthase attenuates the development of seizures in mice

Cited by 31 publications

References 19 publications

Involvement of the Nitric Oxide/Cyclic Guanylate Monophosphate Pathway in the Pilocarpine-Induced Seizure Model in Mice

Involvement of the Nitric Oxide/Cyclic Guanylate Monophosphate Pathway in the Pilocarpine-Induced Seizure Model in Mice

A COX/5-LOX Inhibitor Licofelone Revealed Anticonvulsant Properties Through iNOS Diminution in Mice

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

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