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

Ann Neurol. 2007 Feb;61(2):109-19. doi: 10.1002/ana.21082.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / pharmacology
  • Animals
  • Animals, Newborn
  • Betamethasone / administration & dosage*
  • Betamethasone / pharmacology
  • Brain / drug effects
  • Brain / embryology*
  • Brain / metabolism
  • Deoxyglucose / pharmacokinetics
  • Disease Models, Animal*
  • Drug Administration Schedule
  • Drug Synergism
  • Electroencephalography
  • Female
  • Fetus / drug effects
  • Gestational Age
  • Glucocorticoids / administration & dosage*
  • Glucocorticoids / pharmacology
  • Humans
  • Immunohistochemistry
  • Infant, Newborn
  • N-Methylaspartate / administration & dosage*
  • Pregnancy
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats*
  • Spasms, Infantile / chemically induced*
  • Spasms, Infantile / diagnosis
  • Spasms, Infantile / metabolism
  • Spasms, Infantile / physiopathology

Substances

  • Glucocorticoids
  • Proto-Oncogene Proteins c-fos
  • N-Methylaspartate
  • Adrenocorticotropic Hormone
  • Betamethasone
  • Deoxyglucose