Excitotoxicity in neonatal hypoxia.
Hypoxic-ischemic encephalopathy (HIE) in neonates is a disorder of excessive neuronal excitation that includes seizures, abnormal EEG activity, and delayed failure of oxidative metabolism with elevated levels of lactic acid in the brain. Evidence from experimental models and clinical investigation indicates that HIE is triggered by a profound disruption in the function of glutamate synapses so that re-uptake of glutamate from the synapse is impaired and post-synaptic membranes containing glutamate receptors are depolarized. Severe hypoxemia preferentially depolarizes neuronal membranes, while ischemia probably has greater impact on the activity of glial glutamate re-uptake. Together, severe hypoxia and ischemia trigger a delayed cascade of events that may result in cell death by necrosis and/or apoptosis. Apoptosis is far more prominent in the neonate than in the adult and activation of cysteine proteases such as caspase-3 is a very important pathway in excitotoxic neonatal injury. Understanding the complex molecular networks triggered by an excitotoxic insult in the neonate provides insight into patterns of selective neuronal vulnerability and potential therapeutic strategies.
Johnston
M V
MV
Division of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. Johnston@kennedykrieger.org
D017209:Apoptosis / Q000502:physiology; D001479:Basal Ganglia / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000172:deficiency; D005609:Free Radicals / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000503:physiopathology*; D007231:Infant, Newborn; D028361:Mitochondrial Diseases / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
D003574:Cytochrome c Group; D005609:Free Radicals; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D020169:Caspases; D002118:Calcium