What is the role of excitatory amino acid (EAA) receptor overactivation in the pathogenesis of hypoxic-ischemic encephalopathy (HIE)?

Updated: Jul 18, 2018
  • Author: Santina A Zanelli, MD; Chief Editor: Dharmendra J Nimavat, MD, FAAP  more...
  • Print

Excitatory amino acid (EAA) receptor overactivation plays a critical role in the pathogenesis of neonatal hypoxia-ischemia. During cerebral hypoxia-ischemia, the uptake of glutamate the major excitatory neurotransmitter of the mammalian brain is impaired. This results in high synaptic levels of glutamate and EAA receptor overactivation, including N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4 isoxazole propionate (AMPA), and kainate receptors. NMDA receptors are permeable to Ca++ and Na+, whereas AMPA and kainate receptors are permeable to Na+. Accumulation of Na+ coupled with the failure of energy dependent enzymes such as Na+/ K+ -ATPase leads to rapid cytotoxic edema and necrotic cell death. Activation of NMDA receptor leads to intracellular Ca++ accumulation and further pathologic cascades activation.

EAAs accumulation also contributes to increasing the pace and extent of programmed cell death through secondary Ca++ intake into the nucleus. The pattern of injury seen after hypoxia-ischemia demonstrate regional susceptibility that can be largely explained by the excitatory circuity at this age (putamen, thalamus, perirolandic cerebral cortex). Finally, developing oligodendroglia is uniquely susceptible to hypoxia-ischemia, specifically excitotoxicity and free radical damage. This white matter injury may be the basis for the disruption of long-term learning and memory faculties in infants with hypoxic-ischemic encephalopathy.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!