Clinical Implications of Epigenetic Dysregulation in Perinatal Hypoxic-Ischemic Brain Damage

Placental and fetal hypoxia caused by perinatal hypoxic-ischemic events are major causes of stillbirth, neonatal morbidity, and long-term neurological sequelae among surviving neonates. Brain hypoxia and associated pathological processes such as excitotoxicity, apoptosis, necrosis, and inflammation, are associated with lasting disruptions in epigenetic control of gene expression contributing to neurological dysfunction. Recent studies have pointed to DNA (de)methylation, histone modifications, and non-coding RNAs as crucial components of hypoxic-ischemic encephalopathy (HIE). The understanding of epigenetic dysregulation in HIE is essential in the development of new clinical interventions for perinatal HIE. Here, we summarize our current understanding of epigenetic mechanisms underlying the molecular pathology of HI brain damage and its clinical implications in terms of new diagnostic, prognostic, and therapeutic tools.Fil: Bustelo, Martí. Universidad de Buenos Aires; Argentina. Maastricht University Medical Center; Países Bajos. Universidad Católica de Cuyo - Sede San Juan; ArgentinaFil: Barkhuizen, Melinda. Maastricht University Medical Center; Países BajosFil: van den Hove, Daniel L. A.. Universiteit Maastricht.; Países BajosFil: Steinbusch, Harry Wilhelm. M.. Universiteit Maastricht.; Países BajosFil: Bruno, Martin. Universidad Católica de Cuyo - Sede San Juan; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; ArgentinaFil: Loidl, Cesar Fabian. Universidad Catolica de Cuyo - Sede San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Gavilanes, Antonio W. Danilo. Maastricht University Medical Cente; Países Bajo

Increased EEG delta frequency corresponds to chorioamnionitis-related brain injury

We evaluated the impact of chorioamnionitis on the intrapartal EEG delta frequency in the non-anesthetized preterm sheep. 10 mg intra-amniotic LPS or saline were given 2 or 14 days before preterm birth at gestational day 125. Lambs were delivered by Caesarean section under local anesthesia. A 5-minute EEG depicted delta activity and amplitude, and the relationship between EEG delta activity and both the white matter (WM) and cortical microglial activation and apoptosis was analyzed. EEG delta activity was increased significantly in the 14-day LPS preterm fetuses compared to both preterm control and 2-day LPS animals (p less than 0.05). No differences were seen between controls and the 2-day LPS fetuses. A direct association was demonstrated between EEG delta activity and both cortical microglial activation (r = 0,645, p = 0,024) and apoptosis (r = 0,580, p = 0,048), and between delta and WM activated microglia (r = 0,742, p = 0,006) and apoptosis (r = 0,777, p = 0,003). This study is the first to show a relationship between brain dysfunction and chorioamnionitis-related injury at birth