The long-term goal of this project is to understand the effects of epileptic seizures on the developing brain. During the last grant period, we showed that severe seizures (status epilepticus, SE) can cause neuronal death in the immature brain, and that this death is often apoptotic, but can also be necrotic. The proportion of necrotic death increases with advancing age. Our results suggest that hypoxic neuronal necrosis starts with cytochrome liberation from mitochondria, and requires the activation of a cascade of caspases. The goal of the upcoming grant is to test the hypothesis that seizure-induced neuronal necrosis is an orderly process that does not involve gene expression, RNA or protein synthesis, but does involve the mitochondrial activation of a caspase cascade. This process is triggered by mitochondrial failure that liberates cytochrome C into the cytoplasm, thereby activating caspase-9, then (by specific, energy-sparing proteolysis), caspase-3 from their constitutionally expressed proenzymes. This hypothesis will be tested in P15 rats and in adult mice subjected to status epilepticus induced by lithium and pilocarpine or by kainic acid. We will use electron microscopy immunocytochemistry, biochemistry and other methods to test this sequence of program activation. We also predict that inhibitors of caspase-3 or caspase-9 activity will reduce seizure-induced neuronal necrosis, We expect that transgenic mice with a null mutation for caspase-3 will have less neuronal necrosis than matched controls, while KOs for p53 will not be affected. We also predict that transgenic mice expressing the baculovirus p35 caspase inhibitor will show a reduced amount of Se-induced neuronal necrosis (and apoptosis) in the hippocampus. This will be of great relevance to the problem of seizure-induced brain damage, since a better understanding of the mechanisms involved in seizure induced neuronal necrosis could help to prevent or minimize that damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS013515-26
Application #
6846254
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Stewart, Randall R
Project Start
1978-12-01
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
26
Fiscal Year
2005
Total Cost
$290,227
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Thompson, Kerry W; Suchomelova, Lucie; Wasterlain, Claude G (2018) Treatment of early life status epilepticus: What can we learn from animal models? Epilepsia Open 3:169-179
Dingledine, Raymond; Coulter, Douglas A; Fritsch, Brita et al. (2017) Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data 4:170061
Suchomelova, L; Lopez-Meraz, M L; Niquet, J et al. (2015) Hyperthermia aggravates status epilepticus-induced epileptogenesis and neuronal loss in immature rats. Neuroscience 305:209-24
Wasterlain, Claude G; Naylor, David E; Liu, Hantao et al. (2013) Trafficking of NMDA receptors during status epilepticus: therapeutic implications. Epilepsia 54 Suppl 6:78-80
Naylor, David E; Liu, Hantao; Niquet, Jerome et al. (2013) Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiol Dis 54:225-38
Wasterlain, Claude G; Gloss, David S; Niquet, Jerome et al. (2013) Epileptogenesis in the developing brain. Handb Clin Neurol 111:427-39
Wasterlain, Claude G; Stöhr, Thomas; Matagne, Alain (2011) The acute and chronic effects of the novel anticonvulsant lacosamide in an experimental model of status epilepticus. Epilepsy Res 94:10-7
Wasterlain, Claude G; Baldwin, Roger; Naylor, David E et al. (2011) Rational polytherapy in the treatment of acute seizures and status epilepticus. Epilepsia 52 Suppl 8:70-1
Lopez-Meraz, Maria-Leonor; Wasterlain, Claude G; Rocha, Luisa L et al. (2010) Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. Neurobiol Dis 37:394-402
Lopez-Meraz, Maria-Leonor; Niquet, Jerome; Wasterlain, Claude G (2010) Distinct caspase pathways mediate necrosis and apoptosis in subpopulations of hippocampal neurons after status epilepticus. Epilepsia 51 Suppl 3:56-60

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