fg-9041 and Status-Epilepticus

In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane expression, composition and function of GABAA receptors (GABAARs). For this, the tissue of chronically epileptic rats was collected within 3h of seizure occurrence (≤3h group) or at least 24h after seizure occurrence (≥24h group). A retrospective analysis of seizure frequency revealed that selecting animals on the bases of seizure proximity also grouped animals in terms of overall seizure burden with a higher seizure burden observed in the ≤3h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤3h group) had similar levels of GABAAR at the plasma membrane they showed deficits in inhibitory neurotransmission. By contrast, the tissue obtained from animals experiencing infrequent seizures (≥24h group) had increased plasma membrane levels of GABAAR and showed no deficit in inhibitory function. Together, our findings offer an initial insight into the molecular changes that might help to explain how alterations in GABAAR function can be associated with differential seizure burden. Our findings also suggest that increased plasma membrane levels of GABAAR might act as a compensatory mechanism to more effectively maintain inhibitory function, repress hyperexcitability and reduce seizure burden. This study is an initial step towards a fuller characterization of the molecular events that trigger alterations in GABAergic neurotransmission during chronic epilepsy.

Topics: Animals; Biotinylation; Disease Models, Animal; Excitatory Amino Acid Antagonists; GABA Agonists; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Isoxazoles; Male; Muscarinic Agonists; Neurons; Pilocarpine; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Status Epilepticus; Valine

The role of N-methyl-D-aspartate (NMDA), non-NMDA glutamate, metabotropic and muscarinic receptors in the maintenance of status epilepticus (SE) was investigated. SE induced in rat brain by continuous electrical stimulation to the hippocampus was terminated by intracerebroventricular (i.c.v.) injection of the non-NMDA antagonists DNQX and NBQX, but not by the muscarinic antagonists scopolamine or atropine, or the metabotropic antagonist AP3. The NMDA antagonist, MK-801 suppressed motor seizure activity but did not terminate electrographic seizures when generalized SE was induced, suggesting that both non-NMDA and NMDA receptors maintain generalized convulsive SE. However, when limbic SE was induced, MK-801 also had an anticonvulsant effect suggesting differences in the mechanisms maintaining limbic SE and generalized SE.

Topics: Animals; Anticonvulsants; Atropine; Brain; Cerebral Ventricles; Dizocilpine Maleate; Electric Stimulation; Electroencephalography; Hippocampus; Injections, Intraventricular; Male; Quinoxalines; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, Muscarinic; Scopolamine; Status Epilepticus