Regulation of glutamate transport and neuroinflammation in a term newborn rat model of hypoxic–ischaemic brain injury

Brain and Neuroscience Advances

article

Silvia Pregnolato¹  Hemmen Sabir²  Karen Luyt¹  Kira DA Rienecker⁴  Anthony R Isles⁵  Elavazhagan Chakkarapani¹ 

[1] Department of Neonatal Neurology, Bristol Medical School, University of Bristol;Department of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn;Department of Pediatrics I/Neonatology, University Hospital Essen, University Duisburg Essen;Department of Physical Therapy and Rehabilitation Science, University of California San Francisco;Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University

关键词: Hypoxic–ischemic encephalopathy;    neuroinflammation;    glutamate;    hypoxia–ischaemia;    cerebral ischaemia;    newborn;    neonatal;    brain;   

DOI  :  10.1177/23982128221097568

学科分类：医学（综合）

来源: Sage Journals

【 摘 要 】

In the newborn brain, moderate-severe hypoxia–ischaemia induces glutamate excitotoxicity and inflammation, possibly via dysregulation of candidate astrocytic glutamate transporter ( Glt1 ) and pro-inflammatory cytokines (e.g. Tnfα , Il1β , Il6 ). Epigenetic mechanisms may mediate dysregulation. Hypotheses: (1) hypoxia–ischaemia dysregulates mRNA expression of these candidate genes; (2) expression changes in Glt1 are mediated by DNA methylation changes; and (3) methylation values in brain and blood are correlated. Seven-day-old rat pups ( n  = 42) were assigned to nine groups based on treatment (for each timepoint: naïve ( n  = 3), sham ( n  = 3), hypoxia–ischaemia ( n  = 8) and timepoint for tissue collection (6, 12 and 24 h post-hypoxia). Moderate hypoxic–ischemic brain injury was induced via ligation of the left common carotid artery followed by 100 min hypoxia (8% O 2 , 36°C). mRNA was quantified in cortex and hippocampus for the candidate genes, myelin ( Mbp ), astrocytic ( Gfap ) and neuronal ( Map2 ) markers (qPCR). DNA methylation was measured for Glt1 in cortex and blood (bisulphite pyrosequencing). Hypoxia–ischaemia induced pro-inflammatory cytokine upregulation in both brain regions at 6 h. This was accompanied by gene expression changes potentially indicating onset of astrogliosis and myelin injury. There were no significant changes in expression or promoter DNA methylation of Glt1 . This pilot study supports accumulating evidence that hypoxia–ischaemia causes neuroinflammation in the newborn brain and prioritises further expression and DNA methylation analyses focusing on this pathway. Epigenetic blood biomarkers may facilitate identification of high-risk newborns at birth, maximising chances of neuroprotective interventions.

【 授权许可】

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