1. UCL Institute for Women's Health, Maternal & Fetal Medicine, Perinatal Brain Repair Group, , London, UK;2. UCL School of Pharmacy, , London, UK;3. UCL Institute for Women's Health, Neonatology, , London, UK;4. Department of Chemistry, The Scripps Research Institute, , Jupiter, Florida, USA;5. Department of Neurology, University of Alabama at Birmingham and Birmingham VA. Medical Center, , Birmingham, Alabama, USA;6. UCL Medical School, , London, UK
Abstract:
Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post‐translational modification caused by Ca+2‐regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue‐specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan‐PAD inhibitor Cl‐amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS‐treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl‐amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug‐directed intervention in neurotrauma.
