Sleep and Epilepsy: A Key Role for Nitric Oxide?

Abstract

Summary:Purpose: It has been suggested that nitric oxide (NO) is involved in sleep mechanisms and in the pathophysiology of epilepsy. Data are, however, controversial because it is not clear whether NO facilitates sleep or waking, or whether it exerts pro-or antiepileptic influences.Methods: The question was considered through NO voltammetric measurements and electroencephalographic recordings performed in GAERS rats (Genetic Absence Epilepsy Rat from Strasbourg): an experimental model of "petit-mal" human disease. Regulatory processes of sleep and epilepsy were studied after administration of a NO synthase inhibitor LL-arginine-pnitroanilide (L-ANA) 100 mg/kg i.p.1, a NO donor (SIN-] 100 ng/2 pl i.c.v.), and the antiepileptic drugs used in clinic [valproate (VPA 200 mg/kg i.p.) and ethosuximide (ESM 100 mg/ kg i.p.)I.Results: In GAERS rats, spontaneous circadian organizations of spike-wave discharges and paradoxical sleep (PS) occur in an opposite way; spontaneous NO concentrations are higher during seizures than during wakefulness, slow-wave sleep, and PS, respectively. L-ANA induces a disappearance of NO peak, an epileptic induction, and a loss of PS while SIN-I induces opposite effects. Antiepileptic effects of VPA and ESM are associated with a PS increase and a significant release of NO.Conclusions: These results indicate that NO could be, in GAERS rats, a central piece in the reciprocal inhibitory mechanisms regulating the induction of PS and spike-wave discharges. NO could prevent absence epilepsy and act as an antiepileptic substance in facilitating PS. Antiepileptic efficiency of VPA and ESM may work through their ability to release NO. A track for a new treatment of petit-ma1 disease in children can be envisioned. Key Words: GAERS ratElectroencephalography-Voltammetry-NO sensorAntiepileptic drugs.Nitric oxide (NO) is a gaseous compound produced in brain neuronal elements equimolarly with citrulline and through biochemical processes involving calmodulin/ Ca2+-dependent NO synthase (NOS) (1,2). NO is involved in various physiological and pathological processes, including regulation of the sleep-wake cycle (3-9) and the electroencephalographic manifestation of epilepsy (10-14). Data reported with respect to sleep, wakefulness (W), and epilepsy are controversial because it is not clear whether NO is associated with the maintenance of sleep or wakefulness, whether it acts as a proor an antiepileptic substance (convulsions or absence seizures). Contrasting conclusions relate both to absence seizures (12) and convulsive phenomena elicited either by electrical stimulation (13) For clarification, we used the animal model of GAERS rats (Genetic Absence Epilepsy Rat from Strasbourg) (15), known to exhibit spontaneous seizures characterized by the occurrence of spike-wave discharges (SWDs). These SWDs are phenomena prevalent in cortical and thalamic structures (16) occurring, at least partly, through GABAergic (17) and glutamatergic processes (18). For our purpose, we analyzed in GAERS rats the part played by NO ...

The untranslated region of exon 2 of the human neuronal nitric oxide synthase (NOS1) gene exerts regulatory activity

“…Elevated cytosolic Ca 2+ may induce CaMKII which in turn mediates phosphorylation of CREB family members (Shaywitz and Greenberg, 1999). Valproic acid is a clinically important drug used in the treatment of bipolar disorders and epilepsia, and has been demonstrated to enhance NO release (Faradji et al, 2000;Karabiber et al, 2004). In our study, valproic acid stimulated NOS1 promoter activities, abrogated by an inhibitor of PI-3K (see Fig.…”

Spontaneous Recurrent Absence Seizure-like Events in Wild-Caught Rats

“…An established feature of SWDs in inbred rat strains is diurnal rhythmicity (Van Luijtelaar and Coenen, 1988;Faradji et al, 2000;Smyk et al, 2011). To find out whether wild rat SWDs displayed a diurnal rhythm, we analyzed continuous video/ECoG recording for up to 30 d. All rat groups, including wild rats, displayed increased SWD spike counts (averaged across days) during lights-off compared with lights-on ( Fig.…”

Influence of Sleep and Sleep Deprivation on Ictal and Interictal Epileptiform Activity

“…These modifications might have a connection with the background factors of the “activating” effects of sleep deprivation [23]. Some laboratory studies have implicated nitric oxide, as inhibitory substance of seizure, associating the action of some anticonvulsant for mediating this [24]. However, other studies place it as proconvulsant substance; as in experimental studies with genetic absence occurs at high concentrations, their concentration is high during some seizures and sleep [25].…”