Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation

Smith, S.E.; Man, Connie; Yip, Ping K.; Tang, Ellen; Chapman, A. Chaston; Meldrum, Brian S.

doi:10.1111/j.1476-5381.1996.tb15690.x

Cited by 60 publications

(24 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If the relationship between NOS inhibition and 7-NI concentration is ascertained, it becomes possible to design dosing regimens that produce a specific degree of NOS inhibition. [21]. These studies have relied on empirical dosing of 7-NI due to a lack of pharmacokinetic and pharmacodynamic information.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7‐nitroindazole

Bush

Pollack

2000

Biopharm & Drug Disp

View full text Add to dashboard Cite

Utilization of nitric oxide (NO) synthase (NOS) inhibitors to probe the role of NO in various central nervous system processes requires use of an inhibitor selective for neuronal NOS, and is facilitated by knowledge of the pharmacokinetics of the inhibitor. The present project was undertaken to elucidate the disposition of the selective neuronal NOS inhibitor 7-nitroindazole (7-NI). A simple, specific HPLC assay was developed with requisite sensitivity to quantitate 7-NI in serum after administration of pharmacologically relevant doses. Further experiments were performed to assess the effects of administered dose on 7-NI disposition. 7-NI displayed marked nonlinearity, consistent with saturable elimination, when administered by ip injection in peanut oil. The nonlinearity was related to total dose, but not to the concentration of 7-NI in the vehicle. Binding of 7-NI in rat serum was concentration-independent and does not contribute to the nonlinearity. Various formulations for iv administration of this water-insoluble compound were evaluated; the optimal vehicle, from the standpoint of 7-NI solubility, appeared to inhibit the clearance of 7-NI from the systemic circulation. Considering the nonlinear disposition of 7-NI, knowledge of the pharmacokinetics of this inhibitor is requisite to designing administration protocols to achieve the desired magnitude and duration of NOS inhibition.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7‐nitroindazole

Bush

Pollack

2000

Biopharm & Drug Disp

View full text Add to dashboard Cite

show abstract

“…Subsequently, it was demonstrated that L-arginine, at a dose of 300 mg (i.c.v. ), was anticonvulsant against soundinduced seizures in DBA/2 mice and genetically epilepsyprone rats (18).…”

Section: Discussionmentioning

confidence: 99%

Effects of L-Arginine on Penicillin-Induced Epileptiform Activity in Rats

Marangoz

Bağirici

2001

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

ABSTRACT-It has been suggested that nitric oxide (NO) is involved in the pathophysiology of epilepsy. Data are, however controversial because it is not clear whether NO has pro-or anticonvulsant effects. The aim of this study was to investigate the effects of NO on penicillin G-induced epileptiform activity. The left cerebral cortex was exposed by craniotomy in urethane-anesthetized Wistar rats. The epileptic activity was produced by intraperitoneal injection of penicillin G (3 million U / kg, i.p.). The ECoG (electrocorticogram) activity was displayed on a four-channel recorder. At 39.7 ± 5.4 min after penicillin administration, large amplitude sharp waves appeared in the ECoG. Mean spike frequency and mean spike amplitude were calculated as 29.5 ± 3.2 / min and 865 ± 91 m V, respectively, at the 55th min. 7-Nitroindazole (60 mg/kg, i.p.) injection 30 min before penicillin G administration significantly reduced the latency of epileptiform activity. Intracerebroventricular administration of L-arginine (300 mg/2 ml, i.c.v.) and sodium nitroprusside (100 mg / 2 m l, i.c.v.) suppressed epileptiform activity. Saline (2 ml) and D-arginine (300 mg/ 2 ml, i.c.v.) administration into the cerebral ventricle were completely ineffective on epileptiform activity (P<0.01). These findings suggest that NO may be an endogenous antiepileptic substance.

show abstract

“…The protective action of 7-NI combined with CBZ or PB against amygdala-kindled seizures was not reversed by L-arginine, so the involvement of NO in this particular interaction does not seem probable. It is also unlikely that the ineffectiveness of L-arginine could be associated with the mechanism postulated by Smith et al (6) for sound-induced seizures. Actually, in amygdala-kindled seizures in rats, L-arginine was ineffective in doses up to 500 mg/kg, and the anticonvulsant effects of 7-NI and an AED were not further enhanced by the NO donor.…”

Section: Discussionmentioning

confidence: 94%

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

2000

View full text Add to dashboard Cite

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

show abstract

Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation

Cited by 60 publications

References 51 publications

Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7‐nitroindazole

Pharmacokinetics and protein binding of the selective neuronal nitric oxide synthase inhibitor 7‐nitroindazole

Effects of L-Arginine on Penicillin-Induced Epileptiform Activity in Rats

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

Contact Info

Product

Resources

About