7‐Nitroindazole Differentially Affects the Anticonvulsant Activity of Antiepileptic Drugs Against Amygdala‐Kindled Seizures in Rats

Abstract

Summary:Purpose: The objective of this study was to evaluate the interaction of the preferential brain nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), with conventional antiepileptic drugs (AEDs) against amygdala-kindled seizures in rats. Methods: Experiments were performed on fully kindled rats. Adverse effects were evaluated with the rotorod test, which assesses motor coordination, and the passive-avoidance task, which assesses memory. Plasma levels of AEDs were measured by immunofluorescence. Results: 7-NI (up to 100 mg/kg) failed to modify seizure parameters. However, it reduced the severity and duration of kindled seizures when coadministered with otherwise ineffective doses of carbamazepine (CBZ) (10-20 mg/kg) or phenobarbital (PB) (20 mg/kg). Combinations of 7-NI with valproate (VPA), diphenylhydantoin (DPH), or clonazepam (CLO) were not protective. L-Arginine (500 mg/kg) did not reverse the seizure-suppressing interactions between 7-NI and the conventional AEDs. The combinations of 7-NI and CBZ or PB did not impair performance in the rotorod test. Coadministration of 7-NI with CBZ did not affect long-term memory, and 7-NI given with PB didn't affect the mnemonic effect of PB. Finally, 7-NI did not affect the free plasma levels of CBZ or PB. necessary to produce clonic convulsions in 50% of the a n i m a l s (3). In contrast, 7 -N I did not affect pentylenetetrazol-and kainate-induced seizures (3,4); but it did markedly suppress sound-induced seizures in DBA/2 mice as well as enoxacin-and pentylenetetrazolevoked seizures in mice. It also exerted protective activity in genetically epilepsy-prone rats (5-7), and it enhanced the severity of clonic convulsions and increased lethality produced by soman in rats (8).Researchers have proposed that NO plays an important role in mediating both the physiological and pathophysiological actions of excitatory amino acids. According to Reagan et al. (9), the stress-induced release of glutamate in the hippocampus was partially prevented by NOS inhibitors. It was also reported that kindled seizures caused a significant increase in NOS activity in the supraopticus nucleus (10) and the amygdala (1 1). Moreover, after hippocampal stimulation-evoked kindling, NOS messenger RNA decreased in the dentate granule cell layer and increased in the CA1 and CA3 pyramidal 1112

Endothelial nitric oxide synthase activity involves in the protective effect of ascorbic acid against penicillin-induced epileptiform activity

“…), has an anticonvulsant effect in the different model of experimental epilepsy. 31,53,56 In contrast, Czuczwar et al 57 reported that L-arginine, at a dose of 500 mg/kg, did not affect the convulsive threshold for the clonic phase of PTZinduced seizures. Although, the earlier effect was seen in the L-arginine + ascorbic acid administered group compared with L-arginine administered group, we may conclude that L-arginine (500 mg/kg, i.p.)…”

“…These results are consistent with previously reported findings. 22,31,35,56 The mechanism of these contradictory effects of L-NAME and 7-NI on penicillininduced epileptiform activity is still unclear. However, these apparently divergent data do not exclude either NO might play a different role in various models of epileptic disorders or it may act as an anticonvulsant or as a proconvulsant agent depending on the experimental procedures and particular brain structures involved as suggested by several reports.…”

Changes of [3H]Muscimol, [3H]Flunitrazepam and [3H]MK-801 Binding in Rat Brain by Prolonged Ventricular Infusion of 7-Nitroindazole

“…These results are consistent with the report that the anti-convulsant action of pentobarbital was augmented when co-administered with 7-NI (100 mg/kg, i.p.) against amygdala-kindled seizures in rats (43). Similarly, it has been reported that the potentiation of the anti-convulsant action of barbiturates by pre-treatment with 7-NI in picrotoxin-induced seizures in rats and audiogenic seizures in DBA/2 mice (27,28).…”

Methylmalonate‐induced seizures are attenuated in inducible nitric oxide synthase knockout mice

“…Although it is believed that NO exerts a import role on neuronal hyperexcitability evidenced in several seizure disorders, (De Sarro et al, 1996; Paoletti et al, 1998; Borowicz et al, 2000; Itoh et al, 2004; de Vasconcelos et al, 2004; Kato et al, 2005), it is difficult to make a clear conclusion on the involvement of this free radical in epilepiform activity. The determining factor for such a discrepancy is not known, but one might argue that methodological differences may account for it.…”