Model of infantile spasms induced by N-methyl-D-aspartic acid in prenatally impaired brain

Authors

  • Libor Velíšek MD, PhD,

    Corresponding author
    1. Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY
    2. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY
    • Department of Neurology, AECOM K314, 1300 Morris Park Avenue, Bronx, NY 10461
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  • Kamran Jehle,

    1. Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY
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  • Samantha Asche MS,

    1. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY
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  • Jana Velíšková MD, PhD

    1. Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY
    2. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY
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Abstract

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.

Interpretation

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. Ann Neurol 2007;61:109–119

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