Although epidemiological studies have provided valuable perspectives on temporal lobe epilepsy, the ethical limitations of human research prevent a definitive answer to the important question: is antiepileptic drug (AED) therapy purely symptomatic, or does it affect the natural history of the epilepsy? The proposed experiments use an animal model of temporal lobe epilepsy to determine whether spontaneous epileptic seizures damage the brain and increase the likelihood of more seizures (i.e., promote epileptogenesis), and conversely, whether decreasing the number of seizures with AEDs significantly reduces brain damage and epileptogenesis. The central hypothesis is that prolonged treatment with an AED, which significantly reduces spontaneous epileptic seizures, causes long-term reductions in the frequency and severity of subsequent epileptic seizures after AED withdrawal. The kainate-treated rat, a well-characterized animal model of temporal lobe epilepsy, will be used to determine whether the progressive increase in the frequency ofspontaneous seizures during the months after status epilepticus continues to damage the hippocampus and contributes to epileptogenesis. AEDs (i.e., phenytoin, phenobarbital, and valproate) will be used to block spontaneous epileptic seizures for prolonged periods to determine whether AED therapy reduces epileptogenesis and results in a long-term decrease in spontaneous seizure frequency (i.e., a decrease in frequency that persists after the AED therapy has been withdrawn). A related hypothesis is that prolonged AED treatment reduces neuronal death and other potential markers of hippocampal epileptogenesis. Chronic recording of electrographic seizures, quantitative histopathological studies, and in vitro electrophysiological recording of synaptic and epileptiform events in hippocampal slices will be used to determine if prolonged AED treatment decreases neuronal damage, reorganization of neural circuits, and epileptogenesis. These experiments will provide precise and valuable information regarding the influence of seizure frequency on brain damage and on the propensity for future seizures, which will be important for understanding the mechanisms of epileptogenesis and for making clinical decisions regarding AED therapy and epilepsy surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045144-05
Application #
6985327
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Fureman, Brandy E
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
5
Fiscal Year
2006
Total Cost
$442,374
Indirect Cost
Name
University of Utah
Department
Physiology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kadam, S D; Dudek, F E (2016) Temporal progression of evoked field potentials in neocortical slices after unilateral hypoxia-ischemia in perinatal rats: Correlation with cortical epileptogenesis. Neuroscience 316:232-48
Zayachkivsky, A; Lehmkuhle, M J; Ekstrand, J J et al. (2015) Ischemic injury suppresses hypoxia-induced electrographic seizures and the background EEG in a rat model of perinatal hypoxic-ischemic encephalopathy. J Neurophysiol 114:2753-63
Pitkänen, Asla; Nehlig, Astrid; Brooks-Kayal, Amy R et al. (2013) Issues related to development of antiepileptogenic therapies. Epilepsia 54 Suppl 4:35-43
Scholl, E A; Dudek, F E; Ekstrand, J J (2013) Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat. Neuroscience 252:45-59
Zayachkivsky, A; Lehmkuhle, M J; Fisher, J H et al. (2013) Recording EEG in immature rats with a novel miniature telemetry system. J Neurophysiol 109:900-11
Fawley, J A; Pouliot, W A; Dudek, F E (2012) Pilocarpine-induced status epilepticus and subsequent spontaneous seizures: lack of effect on the number of gonadotropin-releasing hormone-positive neurons in a mouse model of temporal lobe epilepsy. Neuroscience 203:153-9
Ali, Atif; Dua, Yashomati; Constance, Jonathan E et al. (2012) A once-per-day, drug-in-food protocol for prolonged administration of antiepileptic drugs in animal models. Epilepsia 53:199-206
Ekstrand, J J; Pouliot, W; Scheerlinck, P et al. (2011) Lithium pilocarpine-induced status epilepticus in postnatal day 20 rats results in greater neuronal injury in ventral versus dorsal hippocampus. Neuroscience 192:699-707
Kadam, Shilpa D; White, Andrew M; Staley, Kevin J et al. (2010) Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy. J Neurosci 30:404-15
White, Andrew; Williams, Philip A; Hellier, Jennifer L et al. (2010) EEG spike activity precedes epilepsy after kainate-induced status epilepticus. Epilepsia 51:371-83

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