Model of infantile spasms induced by N-methyl-D-aspartic acid in prenatally impaired brain.
OBJECTIVE
Infantile spasms (a catastrophic epileptic syndrome of childhood) are insensitive to classic antiepileptic drugs. New therapies are limited by lack of animal models. Here we develop a new model of flexion spasms based on prenatal exposure to betamethasone combined with postnatal administration of N-methyl-D-aspartic acid (NMDA) and determine brain structures involved in the induction of flexion spasms.


METHODS
Pregnant rats received two doses of betamethasone on day 15 of gestation. Offspring was injected with NMDA on postnatal day 15. Effects of adrenocorticotropin therapy on the development of age-specific flexion spasms were determined and electroencephalographic correlates recorded. C-fos immunohistochemistry and [14C]2-deoxyglucose imaging identified brain structures involved in the development of flexion spasms.


RESULTS
Prenatal betamethasone exposure sensitizes rats to development of NMDA-induced spasms and, most importantly, renders the spasms sensitive to adrenocorticotropin therapy. Ictal electroencephalogram results correspond to human infantile spasms: electrodecrement or afterdischarges were observed. Imaging studies defined three principal regions involved in NMDA spasms: limbic areas (except the dorsal hippocampus), hypothalamus, and the brainstem.


CONCLUSIONS
Despite certain limitations, our new model correlates well with current infantile spasm hypotheses and opens an opportunity for development and testing of new effective drugs.
Velísek
Libor
L
Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. velisek@aecom.yu.edu
Jehle
Kamran
K
Asche
Samantha
S
Velísková
Jana
J
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001623:Betamethasone / Q000008:administration & dosage* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004569:Electroencephalography; D005260:Female; D005333:Fetus / Q000187:drug effects; D005865:Gestational Age; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D016202:N-Methylaspartate / Q000008:administration & dosage*; D011247:Pregnancy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D013036:Spasms, Infantile / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology
D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D016202:N-Methylaspartate; D000324:Adrenocorticotropic Hormone; D001623:Betamethasone; D003847:Deoxyglucose