Phenytoin, phenobarbital, and midazolam fail to stop status epilepticus-like activity induced by low magnesium in rat entorhinal slices, but can prevent its development

Abstract

It was shown previously that low-Mg2+-induced epileptiform activity in rat entorhinal cortex slices changes with time from a pattern of serial seizure-like events (SLEs) to a state of continuously recurring epileptiform activity. Valproic acid blocked the early SLEs but not the late activity. It was proposed that the late activity is a model for pharmacoresistant status epilepticus since it was also refractory to phenytoin, carbamazepine, phenobarbital, and midazolam. In the present study, it is demonstrated that phenytoin (50 microM, n=6), phenobarbital (150 microM, n=7), and midazolam (50 microM, n=5) were able to block the early SLEs but not the late activity at the same concentrations. Carbamazepine (50 microM) reduced the duration of the SLEs from 21 +/-5 s to 4+/-3 s (P<0.01), the interictal interval from 123+/-27 s to 27+/-19 s (P<0.01), the SLE-associated rise of [K+]o from 7.7+/-0.5 mM to 5.7+/-0.8 mM (n=4, P<0.05), and the spread of the SLE between entorhinal cortex and neocortex from 4.0+/-0.6 s to 0.8+/-0.1 s (n=4, P<0.05). Lower concentrations of phenytoin (5 and 10 microM, n=5), carbamazepine (10 microM, n =6), and phenobarbital (50 microM, n = 4) had no effect. In conclusion, the hypothesis is supported that low-Mg2+-induced epileptiform activity in rat entorhinal cortex is an in vitro model for the transition from pharmacosensitive to pharmacoresistant status epilepticus.

What Is the Clinical Relevance of In Vitro Epileptiform Activity?

“…This is an area that can be profi tably studied in vitro, where microscopic imaging during epileptiform activity is more feasible than in vivo. Barbiturates and other anesthetics used to terminate status epilepticus are typically titrated to a burst suppression pattern that is very reminiscent of the periodic population discharges that are observed in acute brain slice preparations exposed to convulsants with anesthetic concentrations of barbiturates [ 23 ]. Indeed, recurrent epileptiform discharges cause considerable cell loss due to mitochondrial depolarization and increased free radical production sensitive to neuroprotection by free radical scavengers such as tocopherol.…”

Feedforward Inhibition Contributes to the Control of Epileptiform Propagation Speed

“…Studies using slices from entorhinal cortex bathed in 0 Mg 2ϩ suggest that failure of feedforward inhibition coincides with an increased resistance to common antiepileptics; thus, it is crucial to understand the mechanisms behind this failure (Dreier and Heinemann, 1990;Pfeiffer et al, 1996;Dreier et al, 1998). This will require additional study because there are several reasons why the feedforward inhibition in late 0 Mg 2ϩ ictal events might fail.…”

Trace Elements and Electrolytes Homeostasis and Their Relation to Antioxidant Enzyme Activity in Brain Hyperexcitability of Epileptic Patients

“…It has been shown previously that low Mg 2+ level-induced epileptiform activity in rat entorhinal cortex slices changes with time from a pattern of serial seizure-like events (SLEs) to a state of continuously recurring epileptiform activity. Low magnesium levels are observed in patients given anticonvulsant drugs designed for the clinical problem of pharmacoresistant epilepsy (76). In addition, efficacy of magnesium sulfate in the prevention and control of eclamptic convulsions has been validated in randomized controlled trials performed worldwide (125 among all groups of epileptics (treated or untreated) and irrespective to the degree of control on AEDs.…”