Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy.

This study compared levetiracetam (Keppra) with reference antiepileptic drugs (AEDs) in the rat pilocarpine model of temporal lobe epilepsy. Electroencephalogram (EEG) recordings showed that i.p. administration of valproate (300 mg/kg), phenobarbital (5 mg/kg) and clonazepam (0.5 mg/kg) all significantly delayed the appearance of the first epileptic spike discharge in hippocampus as well as synchronous epileptiform activity in hippocampus and cortex. In contrast, i.p. administration of levetiracetam (17 mg/kg) only significantly delayed the appearance of the latter. This was corroborated by findings showing that i.p. administration of levetiracetam (17 mg/kg) significantly opposed pilocarpine-induced increases in the amplitude of the orthodromic population spike in the hippocampal CA3 area of urethane-anaesthetised rats, while valproate (200 mg/kg), phenobarbital (10 mg/kg) and clonazepam (1 mg/kg) had no effect. Pre-treatment i.p. with phenobarbital (10 mg/kg) and clonazepam (0.5 mg/kg) significantly reversed seizure-induced changes in aspartate and GABA concentrations while valproate (300 mg/kg) significantly reduced aspartate concentrations further. In contrast, levetiracetam (34 mg/kg) significantly counteracted all seizure-induced alterations in amino acid concentrations. Midazolam induced significant seizure protection after microinjection into substantia nigra pars reticulata (SNR, 50 nmol), nucleus accumbens (NA, 25 nmol) and caudate putamen (CP, 25 nmol), whereas phenytoin (50 nmol) only showed significant seizure protection after injection into the latter area. Levetiracetam differed by significant seizure protection after injection into SNR (1,000 nmol) and NA (3,000 nmol). These results suggest that levetiracetam is distinct from other AEDs by its ability to selectively suppress synchronisation of neuronal spike and burst firing in hippocampus.

Pilocarpine-induced epileptogenesis in the rat: impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations.

This study characterized the electrophysiological and neuropathological changes in rat brains caused by pilocarpine (PILO)-induced status epilepticus (SE) of different duration. SE induced by PILO (375 mg/kg, i.p. adm.) were terminated with a bolus dose of diazepam (10 mg/kg, i.v. adm.) injected 7.5, 15, 30, 60 or 120 min after initiation of the secondary generalization of the SE. Three weeks later, the gain in body weight was significantly reduced in the rats exposed to PILO-induced SE lasting 30 min or more, when compared to controls. Spontaneous seizures were not detected in rats with PILO-induced SE of 7.5 min duration whereas 50 and 25% of the rats exposed to seizure durations of 30 and 120 min expressed motor seizures. Significant alterations reflecting hyperexcitability (increased number of population spikes (PSs)) and reduced paired-pulse inhibition were observed in recordings of hippocampal field potentials from rats with PILO-induced SE of at least 30 min duration. This was substantiated by brain lesions (necrosis in olfactory cortex, hippocampus, amygdala and thalamus) in all rats manifesting a SE of at least 30 min duration. Thus, the results of the present study demonstrate that rats exposed to PILO-induced SE of at least 30 min duration manifest an epileptogenic process, revealed 3 weeks later by several parameters. Among these, hippocampal field potentials appear to represent the most sensitive marker, potentially useful for pharmacological evaluation of drugs with putative antiepileptogenic properties.