7-nitroindazole differentially affects the anticonvulsant activity of antiepileptic drugs against amygdala-kindled seizures in rats.
OBJECTIVE
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.


CONCLUSIONS
Pharmacokinetic interactions do not seem to account for the anticonvulsant effects of 7-NI combined with CBZ or PB. Central nitric oxide (NO) is possibly not involved in the synergism between 7-NI and these AEDs.
Borowicz
K K
KK
Department of Pharmacology and Toxicology, Medical University, Lublin, Poland.
Kleinrok
Z
Z
Czuczwar
S J
SJ
D000679:Amygdala / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004597:Electroshock; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004924:Escape Reaction / Q000187:drug effects; D007191:Indazoles / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000097:blood / Q000517:prevention & control*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D007191:Indazoles; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole