TY - GEN
T1 - Excitotoxicity as a Common Mechanism for Fetal Neuronal Injury with Hypoxia and Intrauterine Inflammation
AU - Burd, I.
AU - Welling, J.
AU - Kannan, G.
AU - Johnston, M. V.
N1 - Funding Information:
This work was supported by NICHD K08HD073315 (I.B.) and NINDSNS28208 (M.V.J.).
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Excitotoxicity
KW - Glutamate
KW - Hypoxic-ischemic encephalopathy
KW - Inflammation
KW - Lipopolysaccharide
KW - Nitric oxide synthase
KW - Periventricular encephalopathy
KW - Prematurity
UR - http://www.scopus.com/inward/record.url?scp=84961218855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961218855&partnerID=8YFLogxK
U2 - 10.1016/bs.apha.2016.02.003
DO - 10.1016/bs.apha.2016.02.003
M3 - Conference contribution
C2 - 27288075
AN - SCOPUS:84961218855
SN - 9780128097458
T3 - Advances in Pharmacology
SP - 85
EP - 101
BT - Neuropsychopharmacology
A2 - Schwarcz, Robert
PB - Academic Press Inc.
ER -