Corticosteroid therapy is widely used during the third trimester of pregnancy to prevent respiratory distress syndrome in prematurely born neonates. A single course of this therapy has no long-term harmful effects. However, multiple courses of corticosteroid therapy with long-lasting elevations of corticosteroids are frequently used. Animal data indicate that long-term prenatal corticosteroid increases during the last third of pregnancy may adversely affect brain development, especially hippocampus-associated functions such as learning and memory. The purpose of this proposal is to establish a rat model of prenatal or early postnatal multiple-course corticosteroid administration to determine the effects of repeated corticosteroid therapy on hippocampal function (tested postnatally in hippocampal- related seizure susceptibility, behavioral and learning tests in vivo) and morphology (assessed using neuronal proliferation, stereological neuronal counts, and rate of neuronal death). The proposal will further investigate the possibility that there may be a synergy between the effects of such doses of corticosteroids that do not produce harmful effects and the effects of another subthreshold postnatal impact (a febrile seizure). The synergy of these two factors will then result in adverse effects on hippocampal function and structure (""""""""two-hit"""""""" hypothesis). Finally, the experiments will determine whether the harmful effects of repeated corticosteroid treatment may be ameliorated by the exposure of the affected offspring to an enriched environment. Methods include prenatal administration of corticosteroids, kainic acid-induced seizures, hippocampal kindling, open field, horizontal bar and elevated plus maze tests, labeling of newly born neurons with BrdU, fluorescent staining for apoptotic/necrotic neurons, stereological neuronal counts in the hippocampus using light and confocal microscopy, and the exposure of the rats to an enriched environment. The data of this proposal will be critical for determining long-term adverse effects of multiple course prenatal corticosteroid therapy and for the ameliorating these effects in the offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS041366-03
Application #
6803019
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Coulombe, James N
Project Start
2002-09-01
Project End
2005-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
3
Fiscal Year
2004
Total Cost
$198,313
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Velíšek, Libor (2011) Prenatal corticosteroid exposure alters early developmental seizures and behavior. Epilepsy Res 95:9-19
Velísek, Libor; Chachua, Tamar; Yum, Mi-Sun et al. (2010) Model of cryptogenic infantile spasms after prenatal corticosteroid priming. Epilepsia 51 Suppl 3:145-9
Coppola, Antonietta; Moshé, Solomon L (2009) Why is the developing brain more susceptible to status epilepticus? Epilepsia 50 Suppl 12:25-6
Velisek, Libor (2008) Age, sex, and hormonal status can be additional variables in prenatal dexamethasone exposure. Neurosci Res 61:333-4
Veliskova, Jana; Chudomel, Ondrej; Poon, Ka Lai et al. (2007) The involvement of the substantia nigra pars reticulata in hypoglycemic seizures. Epilepsia 48 Suppl 5:106-8
Velisek, Libor; Jehle, Kamran; Asche, Samantha et al. (2007) Model of infantile spasms induced by N-methyl-D-aspartic acid in prenatally impaired brain. Ann Neurol 61:109-19
Veliskova, Jana; Velisek, Libor (2007) Beta-estradiol increases dentate gyrus inhibition in female rats via augmentation of hilar neuropeptide Y. J Neurosci 27:6054-63
Veliskova, Jana (2007) Estrogens and epilepsy: why are we so excited? Neuroscientist 13:77-88
Velisek, Libor (2006) CNS aspects of prenatal drug exposure: drugs of abuse, toxins, and corticosteroids. Ann N Y Acad Sci 1074:577-89
Kirchner, Anne; Veliskova, Jana; Velisek, Libor (2006) Differential effects of low glucose concentrations on seizures and epileptiform activity in vivo and in vitro. Eur J Neurosci 23:1512-22

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