Excitotoxicity as a Common Mechanism for Fetal Neuronal Injury with Hypoxia and Intrauterine Inflammation

I. Burd, J. Welling, G. Kannan, M. V. Johnston

Research output: Chapter in Book/Report/Conference proceedingConference contribution


Excitotoxicity is a mechanism of neuronal injury, implicated in the pathogenesis of many acute and chronic neurologic disorders, including perinatal brain injury associated with hypoxia-ischemia and exposure to intrauterine inflammation. Glutamate, the primary excitatory neurotransmitter, signals through N-methyl-. d-aspartic acid (NMDA)/α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. Proper functioning of both of these receptors, in conjunction with glutamate signaling, is crucial for normal development. However, even a small imbalance can result in perinatal neuronal injury. Therefore, a mechanistic understanding of the role of excitotoxicity and the NMDA/AMPA receptor functions is critical to establishing the pathogenesis of hypoxic-ischemic encephalopathy (HIE) and perinatal brain injury due to exposure to intrauterine inflammation. Evidence from experimental animal models and clinical studies indicates that both oxygen and glucose deficiencies play a major role in fetal neuronal injury. However, the connection between these deficiencies, excitotoxicity, and HIE is not well established. The excitotoxic mechanisms in animal models and humans have many parallels, suggesting that detailed animal studies can elicit clinically relevant discoveries. While current therapies for HIE include hypothermia and other neuroprotective measures, emphasizing prevention of acute injuries, increase of therapeutic time window, and increased neural repair, there are no effective widely used treatment modalities for fetuses and neonates exposed to intrauterine inflammation. Further studies of HIE and intrauterine inflammation (as in cases of preterm birth and chorioamnionitis) will provide a better insight into development of effective therapeutic interventions for these conditions.

Original languageEnglish (US)
Title of host publicationNeuropsychopharmacology
Subtitle of host publicationA Tribute to Joseph T. Coyle, 2016
EditorsRobert Schwarcz
PublisherAcademic Press Inc.
Number of pages17
ISBN (Print)9780128097458
StatePublished - 2016

Publication series

NameAdvances in Pharmacology
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925


  • Excitotoxicity
  • Glutamate
  • Hypoxic-ischemic encephalopathy
  • Inflammation
  • Lipopolysaccharide
  • Nitric oxide synthase
  • Periventricular encephalopathy
  • Prematurity

ASJC Scopus subject areas

  • Pharmacology


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