Reactive oxygen species in status epilepticus.

There has been growing evidence for a critical role of oxidative stress in neurodegenerative disease, providing novel targets for disease modifying treatments. Although antioxidants have been suggested and tried in the treatment of epilepsy, it is only recently that the pivotal role of oxidative stress in the pathophysiology of status epilepticus has been recognized. Although conventionally thought to be generated by mitochondria, reactive oxygen species during status epilepticus and prolonged seizure are generated mainly by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (stimulated by NMDA receptor activation). Excessive production of reactive oxygen species results in lipid peroxidation, DNA damage, enzyme inhibition, and mitochondrial damage, culminating in neuronal death. Antioxidant therapy has been hampered by poor CNS penetration and rapid consumption by oxidants. However, alternative approaches such as inhibiting NADPH oxidase or increasing endogenous antioxidant defenses through activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) could avoid these problems. Small molecules that increase Nrf2 activation have proven to be not only effective neuroprotectants following status epilepticus, but also potently antiepileptogenic. There are "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

A comparative electrographic analysis of the effect of sec-butyl-propylacetamide on pharmacoresistant status epilepticus.

Better treatment of status epilepticus (SE), which typically becomes refractory after about 30 min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. Using a previously-published algorithm, the effects of SPD on ESE were compared quantitatively to other relevant compounds. To confirm benzodiazepine resistance, diazepam (DZP) was shown to suppress ESE when administered 15 min after the first motor seizure, but not after 30 min (100mg/kg). VPA (300 mg/kg) also lacked efficacy at 30 min. SPD (130 mg/kg) strongly suppressed ESE at 30 min, less after 45 min, and not at 60 min. At a higher dose (180 mg/kg), SPD profoundly suppressed ESE at 60 min, similar to propofol (100mg/kg) and pentobarbital (30 mg/kg). After 4-6h of SPD-induced suppression, EEG activity often overshot control levels at 7-12h. Valnoctamide (VCD, 180 mg/kg), an SPD homolog, was also efficacious at 30 min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1h after the first motor seizure. SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.