Additive Anticonvulsive Effects of Sumatriptan and Morphine on Pentylenetetrazole-Induced Clonic Seizures in Mice.

Background and Purpose: Sumatriptan protects the brain from damage and enhance the anti-seizure effect of morphine. There is evidence that nitric oxide (NO) may mediate these effects of both drugs. In the present study, we investigated the effects of sumatriptan (0.1-20 mg/kg, intraperitoneal [i.p.]) and morphine (0.1-20 mg/kg, i.p.) alone or in combination on seizure thresholds in an in vivo model of seizure in mice. Using various NO synthase inhibitors as well as the NO precursor, we assessed possible involvement of NO signaling in these effects. Methods: Clonic seizures were induced in male Naval Medical Research Institute mice by intravenous administration of pentylenetetrazol (PTZ). Results: Acute sumatriptan administration exerted anti-convulsive effects at 0.5 (p<0.01) and 1 mg/kg (p<0.05), but pro-convulsive effects at 20 mg/kg (p<0.05). Morphine had anti-convulsive effects at 0.5 (p<0.05) and 1 mg/kg (p<0.001), but exerted pro-convulsive effect at 20 mg/kg (p<0.05). Combination treatment with sub-effective doses of sumatriptan (0.1 mg/kg) and morphine (0.1 mg/kg) significantly (p<0.05) exerted an anti-convulsive effect. Co-administration of the NO precursor L-arginine (60 mg/kg) with sub-effective doses of sumatriptan and morphine significantly (p<0.05) increased seizure threshold compared with sumatriptan alone, but not sumatriptan+morphine group. While concomitant administration of either the non-selective NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (5 mg/kg) or the selective inducible NOS inhibitor aminoguanidine (50 mg/kg) with combined sub-effective doses of morphine and sumatriptan produced significant anticonvulsive effects, concomitant administration with the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg) inhibited this effect. Conclusions: Our data suggest a possible role for the NO signaling in the anticonvulsive effects of combined sumatriptan and morphine on the PTZ-induced clonic seizures in mice.

Involvement of N-Methyl-D-Aspartate Receptors in the Anticonvulsive Effects of Licofelone on Pentylenetetrazole-Induced Clonic Seizure in Mice.

BACKGROUND AND PURPOSE: Licofelone is a dual 5-lipoxygenase/cyclooxygenase inhibitor, with well-documented anti-inflammatory and analgesic effects, which is used for treatment of osteoarthritis. Recent preclinical studies have also suggested neuroprotective and anti-oxidative properties of this drug in some neurological conditions such as seizure and epilepsy. We have recently demonstrated a role for nitric oxide (NO) signaling in the anti-epileptic activity of licofelone in two seizure models in rodents. Given the important role of N-methyl-D-aspartate receptors (NMDARs) activation in the NO production and its function in the nervous system, in the present study, we further investigated the involvement of NMDAR in the effects of licofelone (1, 3, 5, 10, and 20 mg/kg, intraperitoneal [i.p.]) in an in vivo model of seizure in mice. METHODS: Clonic seizures were induced in male NMRI mice by intravenous administration of pentylenetetrazol (PTZ). RESULTS: Acute administration of licofelone exerted anticonvulsant effects at 10 (p<0.01) and 20 mg/kg (p<0.001). A combined treatment with sub-effective doses of the selective NMDAR antagonist MK-801 (0.05 mg/kg, i.p.) and licofelone (5 mg/kg, i.p.) significantly (p<0.001) exerted an anticonvulsant effect on the PTZ-induced clonic seizures in mice. Notably, pre-treatment with the NMDAR co-agonist D-serine (30 mg/kg, i.p.) partially hindered the anticonvulsant effects of licofelone (20 mg/kg). CONCLUSIONS: Our data suggest a possible role for the NMDAR in the anticonvulsant effects of licofelone on the clonic seizures induced by PTZ in mice.

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

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.

Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2.

Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR-gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARγ agonist, potentiated the anticonvulsant effects of WIN, while PPARγ antagonist inhibited these anticonvulsant effects partially. On the other hand PPARα antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARα antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility.

Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice.

Thalidomide is an old glutamic acid derivative which was initially used as a sedative medication but withdrawn from the market due to the high incidence of teratogenicity. Recently, it has reemerged because of its potential for counteracting number of diseases, including neurodegenerative disorders. Other than the antiemetic and hypnotic aspects, thalidomide exerts some anticonvulsant properties in experimental settings. However, the underlying mechanisms of thalidomide actions are not fully realized yet. Some investigations revealed that thalidomide could elicit immunomodulatory or neuromodulatory properties by affecting different targets, including cytokines (such as TNF α), neurotransmitters, and nitric oxide (NO). In this regard, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of thalidomide is affected through modulation of the l-arginine-nitric oxide pathway or not. Injection of a single effective dose of thalidomide (10 mg/kg, i.p. or higher) significantly increased the seizure threshold (P<0.05). On the one hand, pretreatment with low and per se noneffective dose of l-arginine [NO precursor] (10, 30 and 60 mg/kg) prevented the anticonvulsant effect of thalidomide. On the other hand, NOS inhibitors [l-NAME and 7-NI] augmented the anticonvulsant effect of a subeffective dose of thalidomide (1 and 5 mg/kg, i.p.) at relatively low doses. Meanwhile, several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of thalidomide significantly. In summary, our findings demonstrated that the l-arginine-nitric oxide pathway can be involved in the anticonvulsant properties of thalidomide, and the role of constitutive nNOS is prominent in the reported neuroprotective feature.