Regulation of glutamate transport and inflammation in newborn brain injuries

Abstract

Background:
Newborn brain injury is the leading cause of childhood neurodisability, including cerebral palsy (CP). Cystic periventricular leukomalacia (cPVL) selectively affects preterm newborns. Hypoxic-ischemic encephalopathy (HIE) affects term newborns with childbirth complications disrupting blood/oxygen supply to the brain. Glutamate excitotoxicity and inflammation are key mechanisms of injury. The role of genetic and epigenetic factors in regulation of glutamate transport and inflammation is unclear. Hypotheses:
1) Preterm survivors with risk variants at the glutamate transporter (EAAT2) and key proinflammatory cytokines (TNFα, IL1ß, IL6) have higher risk of impairment vs those with either variant or none
2) Hypoxia-ischaemia (HI) alters transcription of these genes in the term-equivalent rat brain
3) This is mediated by a DNA methylation change in the brain, which correlates with methylation in blood

Methods:
In the APIP cohort (n=308), genotypes were tested for association with CP at 2y; secondary outcomes included cPVL, and standardised motor and cognitive assessments at 2y (Griffiths Scales) and 5y (Movement ABC; British Ability Scales, BAS). In the rat study (n=42), the effects of HI on transcription of these genes were assessed in the cortex and hippocampus (qPCR), alongside DNA methylation of EAAT2 and TNFα in cortex and blood (bisulfite pyrosequencing)

Results:
Cytokine variants are associated with cPVL and CP (TNFα -308) and the BAS cognitive score (IL1ß -511). Evidence was weaker for white matter injury (IL6 -174), the non-verbal and verbal BAS subscales (IL1ß -511 and EAAT2 -200/-181 respectively). HI induced cytokine transcription in the rat brain, accompanied by astrogliosis and myelin injury. Evidence of suppression of glutamate transport in the cortex was very weak and not associated with DNA methylation changes.

Conclusions:
These exploratory studies support a role for neuroinflammation in neurological and neurodevelopmental impairment. Genetic and epigenetic biomarkers may facilitate early identification of high-risk newborns maximising chances of prevention and treatment.

Date of Award	23 Mar 2021
Original language	English
Awarding Institution	The University of Bristol
Supervisor	Karen Luyt (Supervisor), Elavazhagan Chakkarapani (Supervisor) & Anthony R. Isles (Supervisor)