Sleep and epilepsy: A key role for nitric oxide?

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 [L-arginine-pnitroanilide (L-ANA) 100 mg/kg i.p.], a NO donor(SIN-1 100 ng/2 mu l 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.)]. 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-1 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-mal disease in children can be envisioned.