PMID- 31068830
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210109
IS  - 1664-042X (Print)
IS  - 1664-042X (Electronic)
IS  - 1664-042X (Linking)
VI  - 10
DP  - 2019
TI  - Glutamate Transport and Preterm Brain Injury.
PG  - 417
LID - 10.3389/fphys.2019.00417 [doi]
LID - 417
AB  - Preterm birth complications are the leading cause of child death worldwide and a 
      top global health priority. Among the survivors, the risk of life-long 
      disabilities is high, including cerebral palsy and impairment of movement, 
      cognition, and behavior. Understanding the molecular mechanisms of preterm brain 
      injuries is at the core of future healthcare improvements. Glutamate 
      excitotoxicity is a key mechanism in preterm brain injury, whereby the 
      accumulation of extracellular glutamate damages the delicate immature 
      oligodendrocytes and neurons, leading to the typical patterns of injury seen in 
      the periventricular white matter. Glutamate excitotoxicity is thought to be 
      induced by an interaction between environmental triggers of injury in the 
      perinatal period, particularly cerebral hypoxia-ischemia and 
      infection/inflammation, and developmental and genetic vulnerabilities. To avoid 
      extracellular build-up of glutamate, the brain relies on rapid uptake by 
      sodium-dependent glutamate transporters. Astrocytic excitatory amino acid 
      transporter 2 (EAAT2) is responsible for up to 95% of glutamate clearance, and 
      several lines of evidence suggest that it is essential for brain functioning. 
      While in the adult EAAT2 is predominantly expressed by astrocytes, EAAT2 is 
      transiently upregulated in the immature oligodendrocytes and selected neuronal 
      populations during mid-late gestation, at the peak time for preterm brain injury. 
      This developmental upregulation may interact with perinatal hypoxia-ischemia and 
      infection/inflammation and contribute to the selective vulnerability of the 
      immature oligodendrocytes and neurons in the preterm brain. Disruption of EAAT2 
      may involve not only altered expression but also impaired function with reversal 
      of transport direction. Importantly, elevated EAAT2 levels have been found in the 
      reactive astrocytes and macrophages of human infant post-mortem brains with 
      severe white matter injury (cystic periventricular leukomalacia), potentially 
      suggesting an adaptive mechanism against excitotoxicity. Interestingly, EAAT2 is 
      suppressed in animal models of acute hypoxic-ischemic brain injury at term, 
      pointing to an important and complex role in newborn brain injuries. Enhancement 
      of EAAT2 expression and transport function is gathering attention as a potential 
      therapeutic approach for a variety of adult disorders and awaits exploration in 
      the context of the preterm brain injuries.
FAU - Pregnolato, Silvia
AU  - Pregnolato S
AD  - Department of Neonatal Neurology, Translational Health Sciences, Bristol Medical 
      School, University of Bristol, Bristol, United Kingdom.
FAU - Chakkarapani, Elavazhagan
AU  - Chakkarapani E
AD  - Department of Neonatal Neurology, Translational Health Sciences, Bristol Medical 
      School, University of Bristol, Bristol, United Kingdom.
FAU - Isles, Anthony R
AU  - Isles AR
AD  - Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and 
      Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
FAU - Luyt, Karen
AU  - Luyt K
AD  - Department of Neonatal Neurology, Translational Health Sciences, Bristol Medical 
      School, University of Bristol, Bristol, United Kingdom.
LA  - eng
GR  - MR/L010305/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Review
DEP - 20190424
PL  - Switzerland
TA  - Front Physiol
JT  - Frontiers in physiology
JID - 101549006
PMC - PMC6491644
OTO - NOTNLM
OT  - EAAT2
OT  - GLT-1
OT  - SLC1A2
OT  - brain injury
OT  - excitotoxicity
OT  - glutamate
OT  - inflammation
OT  - preterm infant
EDAT- 2019/05/10 06:00
MHDA- 2019/05/10 06:01
PMCR- 2019/04/24
CRDT- 2019/05/10 06:00
PHST- 2018/10/15 00:00 [received]
PHST- 2019/03/27 00:00 [accepted]
PHST- 2019/05/10 06:00 [entrez]
PHST- 2019/05/10 06:00 [pubmed]
PHST- 2019/05/10 06:01 [medline]
PHST- 2019/04/24 00:00 [pmc-release]
AID - 10.3389/fphys.2019.00417 [doi]
PST - epublish
SO  - Front Physiol. 2019 Apr 24;10:417. doi: 10.3389/fphys.2019.00417. eCollection 
      2019.