Abstracts

Animal studies suggest a role of nitric oxide (NO) in the pathogenesis of epilepsy, but little is known about the role of NO in human epilepsy. In this study, (1) we compare the effect of NOS inhibition on 0 Mg²⁺-induced epileptiform field potentials (EFP) recorded from the hippocampus (CA1) and the neocortex of rat brain slices, (2) we investigate the effect of NOS inhibition on EFP in epileptic-focal, compared to non-epileptic human neocortex, and (3) correlate the effect of NOS inhibition in human neocortex with the response to NR2B-specific NMDA receptor inhibition. Rat brain slices (n = 4) were prepared from male Sprague Dawley rats. Human neocortical tissue was acquired from 14 patients undergoing epilepsy surgery. Epileptic samples (n = 7) were taken from the seizure onset zone of patients with cortical dysplasia. Non-epileptic tissue (n = 7) was acquired from lateral temporal neocortex of patients with hippocampal sclerosis and normal neocortical MRI and histopathology. Zero Mg²⁺-induced EFP were recorded. The NOS inhibitors 7-nitroindazole (NI; 250 [micro]M) or nitro-L-arginine-methylester (L-NAME; 200 [micro]M), and the NO donor S-nitroso-N-acetylpenicillamine (SNAP; 200 [micro]M) were applied. In four experiments, the NR2B-subunit specific NMDA receptor inhibitor ifenprodil (10 [micro]M) was applied. The following burst parameters were measured: repetition rate, burst duration, and burst integral. In rat slices, NOS inhibition with 7-NI (n = 2) or L-NAME (n = 2) suppressed EFP in the hippocampus (CA1) and reduced repetition rate, duration and integral of EFP in the neocortex. In epileptic human slices, 7-NI (n = 9) and L-NAME (n = 4) reduced the duration and integral of EFP, without affecting repetition rate. The effects of 7-NI and L-NAME were reversible after washout with 0 Mg²⁺ ACSF or after addition of SNAP (n = 3). In non-epileptic human slices, none of the burst parameters was significantly changed with application of either 7-NI (n = 8 slices) or L-NAME (n = 4). Addition of SNAP had no measurable effect. Ifenprodil suppressed EFP in dysplastic epileptic (n = 2), but not in non-epileptic (n = 2) slices. Our results suggest: (1) NO is essential for neuronal synchronization in normal rat hippocampus, but not in the normal neocortex. (2) In human epileptic dysplastic neocortex, NO delays the repolarization of EFP. In non-epileptic human cortex, NO has no considerable effect on various burst parameters. (3) The NOS-NO pathway is linked to NMDA receptor activation; sensitivity of EFP to NOS inhibition correlates with their sensitivity to NR2B-specific NMDA receptor inhibition. (Supported by NIH 1R21 NS42354, NIH K08 NS02046 to IN; NIH 2RO1 HL51614, NIH RO1 NS43284 to DJ; IMF, University of Munster, Germany (MO 620202) to GM.)