Ischemia in the developing brain triggers a series of events that cause damage after a threshold of severity and duration are reached. Release of glutamate, the major excitatory amino acid neurotransmitter in the brain, is one of the primary events in this cascade of injury. Release of glutamate combined with reversal of glutamate uptake pumps in nerve terminals causes glutamate levels to increase from 10–1000x baseline levels in the brain's extracellular space during ischemia, traumatic brain injury, and hypoglycemia in animal models and in humans. High levels of extracellular glutamate trigger opening of N‐methyl‐D‐asparate (NMDA) and non‐NMDA glutamate channels, allowing calcium and sodium to flood into neurons. Energy failure in mitochondria facilitates opening of NMDA channels by lowering the membrane potential and reducing their blockade by magnesium that resides within the channel at normal membrane potentials. Calcium entry into the cytoplasm triggers several events including activation of lipases, proteases, and nucleases that can destroy the neuron's cellular machinery. Generation of reactive oxygen free radicals including the messenger molecule nitric oxide can have additional destructive effects. Drugs that block glutamate receptors and the “excitotoxic cascade” of downstream events can protect the brain from injury and show promise for clinical application in infants and children. © 1995 Wiley‐Liss, Inc.
|Original language||English (US)|
|Number of pages||8|
|Journal||Mental Retardation and Developmental Disabilities Research Reviews|
|State||Published - 1995|
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Neuropsychology and Physiological Psychology