Nitric oxide regulates excitatory amino acid release in a biphasic manner in freely moving rats

The effect of altering hippocampal nitric oxide levels on basal and N-methyl-d-aspartate (NMDA) receptor-evoked release of glutamate and aspartate has been studied in freely moving rats. NMDA increased extracellular glutamate and aspartate in a concentration-dependent manner. The nitric oxide synthase inhibitor l-nitro-arginine-methyl ester (l-NAME; 100 μM) increased basal glutamate and aspartate release, and also enhanced release of these amino acids evoked by NMDA (100 μM) compared with the same concentration of NMDA infused alone. l-NAME at 200 μM increased basal dialysate glutamate, but not aspartate, to a lesser extent than the 100 μM concentration of the drug, and the NMDA-induced release of glutamate and aspartate was decreased. l-NAME at 1.0 mM did not significantly alter basal extracellular glutamate but significantly decreased dialysate aspartate, while abolishing the NMDA-evoked release of both amino acids. The actions of l-NAME were not mimicked by its much less active isomer d-nitro-arginine-methyl ester. The nitric oxide donor drug S-nitroso-N-penicillamine decreased dialysate glutamate and aspartate at a 500 μM concentration but increased the extracellular level of both amino acids when infused at 1.0 mM and 2.0 mM concentrations. These data suggest that nitric oxide may mediate both excitatory and inhibitory functions, according to the level of nitric oxide production in vivo

Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo

The effect of altering hippocampal nitric oxide (NO) levels on basal and N-methyl-d-aspartate receptor-evoked release of GABA has been studied in freely moving rats. N-Methyl-d-aspartate (NMDA) increased extracellular GABA in a concentration-dependent manner. The nitric oxide synthase inhibitor t-nitro-arginine-methyl ester (l-NAME; 100 μM) increased basal GABA release, and also enhanced release of GABA evoked by NMDA (100 μM) compared with the same concentration of NMDA infused alone. 200 μM l-NAME increased basal dialysate GABA, but to a lesser extent than the 100 μM concentration of the drug, and the NMDA-induced release of GABA was decreased. 1.0 MM l-NAME significantly decreased basal extracellular GABA, while abolishing the NMDA-evoked release of the amino acid. The actions of l-NAME were not mimicked by its much less active isomer d-nitro-arginine-methyl ester. The NO donor S-nitroso-N-acetylpenicillamine decreased dialysate GABA at a 500 μM concentration but increased the extracellular level of the transmitter when infused at 1.0 and 2.0 mM concentrations. These data suggest that NO may mediate both excitatory and inhibitory functions in vivo

Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial

Background: Additional options are needed for monotherapy treatment of adults newly diagnosed with partial epilepsy. This trial compares the efficacy and tolerability of once-daily zonisamide with twice-daily controlled-release carbamazepine monotherapy for such patients. Methods: In this phase 3, randomised, double-blind, parallel-group, non-inferiority trial, adults from 120 centres in Asia, Australia, and Europe, aged 18–75 years and newly diagnosed with partial epilepsy, were randomly assigned (in a 1:1 ratio, done with a computer-generated pseudorandom code) to receive zonisamide or carbamazepine. Patients, investigators, and sponsor personnel giving drugs, analysing outcomes, and interpreting data were masked to treatment allocation. After treatment initiation (zonisamide 100 mg/day vs carbamazepine 200 mg/day [given in two doses]) and up-titration (to 300 mg/day vs 600 mg/day), patients entered a 26–78 weeks flexible-dosing period (200–500 mg/day vs 400–1200 mg/day, according to response and tolerance). Once patients were seizure-free for 26 weeks they entered a 26-week maintenance phase. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00477295. Findings: 583 patients were randomly assigned to treatment groups (282 zonisamide, 301 carbamazepine), of whom 456 were analysed for the primary endpoint (per-protocol population: 223 zonisamide, 233 carbamazepine). 177 of 223 (79·4%) patients in the zonisamide group and 195 of 233 (83·7%) patients in the carbamazepine group were seizure-free for 26 weeks or more (adjusted absolute treatment difference −4·5%, 95% CI −12·2 to 3·1). The incidence of treatment-emergent adverse events was 170 (60%) in the zonisamide group versus 185 (62%) in the carbamazepine group, of which 15 (5%) versus 17 (6%) were serious and 31 (11%) versus 35 (12%) led to withdrawal. Interpretation: Zonisamide was non-inferior to controlled-release carbamazepine—according to International League Against Epilepsy guidelines—and could be useful as an initial monotherapy for patients newly diagnosed with partial epilepsy