Status epilepticus (SE) is a prolonged, self-sustaining seizure that can result in brain damage, impaired cognition, systemic complications and death. Many patients in SE do not respond to benzodiazepines, which are the only established treatment of this neurological emergency. A better understanding of the cellular and molecular mechanisms that sustain SE can lead to identification of novel therapeutic targets and therapies. In preliminary studies, hippocampal slices were prepared from animals in diazepam refractory or late stage of SE or controls and AMPA receptor (AMPAR)-mediated EPSCS were recorded from CA1pyramidal neurons or dentate granule cells (DGCs). There was a rapid change in the rectification properties of AMPA mediated EPSCs became philanthotoxin sensitive. In biochemical analysis GluR2 subunit surface expression was reduced compared in SE-treated animals to that in control animals. There was evidence of Ca2+ entry through calcium permeable AMPARs during in vitro recurrent bursting. The noncompetitive AMPAR antagonist GYKI5466 terminated SE that was refractory to benzodiazepine treatment. We propose to test the hypothesis hypothesis that during SE, AMPARs on principal hippocampal neurons are rapidly and dynamically modified from GluR2- containing to GluR2-lacking receptors, thus creating CP-AMPARs in four aims.
In aim 1, we seek to define the time course of modification of AMPAR-mediated transmission.
In aim 2, experiments test whether Ca2+ can enter hippocampal neurons during seizures via CP- AMPARs.
In aim 3, experiments to test whether prolonged seizures and in vitro bursting accelerates internalization of the GluR2 subunit of AMPARs.
In aim 4, experiments will compare the efficacy of competitive and non-competitive AMPAR antagonists and therapeutically available topiramate in terminating early, refractory and late SE. Proposed plan will open a new area of investigation into the pathophysiology and treatment of SE.

Public Health Relevance

Status epilepticus is a prolonged, self-sustaining seizure that can result in brain damage, impaired cognition, systemic complications and death. A better understanding of the cellular and molecular mechanisms that sustain status epilepticus can lead to the identification of novel treatments. We propose to test a new mechanism of status epilepticus and propose a new treatment based on this mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040337-10
Application #
8220717
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2000-09-15
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$336,875
Indirect Cost
$118,125
Name
University of Virginia
Department
Neurology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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