endothelin-1 and Cerebral-Palsy

There is a growing body of evidence from clinical and epidemiologic studies that in utero exposure to infection plays an important role in the genesis of fetal or neonatal injury leading to cerebral palsy and chronic lung disease. Thus, after chorioamnionitis the incidence of immature neonates with periventricular white matter damage and periventricular or intraventricular hemorrhage is significantly elevated. Recent clinical and experimental data support the hypothesis that a fetal inflammatory response links antenatal infection with brain white matter damage and subsequent motor handicap. A variety of studies support the view that cytokines released during intrauterine infection directly cause injury to the immature brain. In this review, we provide evidence that in utero exposure to bacterial infection can severely alter fetal cardiovascular function, resulting in dysregulation of cerebral blood flow and subsequent hypoxic-ischemic brain injury.

Topics: Animals; Cardiovascular System; Cerebral Hemorrhage; Cerebral Palsy; Cytokines; Endothelin-1; Endotoxemia; Endotoxins; Female; Fetal Diseases; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Newborn, Diseases; Nitric Oxide; Pregnancy; Pregnancy Complications, Infectious

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.

Topics: Animals; Animals, Newborn; Association Learning; Atrophy; Brain Ischemia; Cell Count; Cerebral Cortex; Cerebral Palsy; Cognition Disorders; Corpus Striatum; Disease Models, Animal; Endothelin-1; Inflammation; Injections; Microglia; Movement Disorders; Neurons; Perceptual Disorders; Rats; Rats, Sprague-Dawley; Rotarod Performance Test; Vasoconstrictor Agents; White Matter

To investigate the levels of endothelial constricting and dilating mediators in preterm infants with hypoxic-ischaemic encephalopathy and prospectively evaluate the association between levels measured during the perinatal period and the diagnosis of neurodevelopmental disorders at 3 years of age.. This regional observational cohort study was conducted at the Azerbaijan Medical University, Baku, Azerbaijan, from November 2011 to January 2013, and comprised very-low-birth-weight infants admitted to the intensive care unit during the perinatal period. Blood concentrations of nitric oxide, endothelin-1 and endothelial nitric oxide synthase were measured on days 1-3 and 5-7 of the neonatal period. Concentrations of neuron-specific enolase and antibodies against N-methyl-D-aspartate glutamate receptors were measured in peripheral blood samples for detection of brain damage in the early neonatal period of life. The infants were divided in 3 different groups: those diagnosed with moderate-to-severe neurodevelopmental disorders or cerebral palsy were included in the first group; those with mild neurologic changes were in the second group; and children without evidence of neurological impairment were in the third group. The fourth group comprised controls. SPSS 20 was used for data analysis.. Of the 62 participants, there were 8(12.9%) in the first group, 20(32.3%) in second, 14(22.6%) in third and 20(32.3%) in the control group. The activity of endothelial nitric oxide synthase was reduced and nitric oxide concentrations were increased in the first group compared to those in the third group (p<0.05). Deep endothelial nitric oxide synthase depression and insufficient endothelin-1 synthesis were associated with diagnosis in the first group (p<0.05). No differences in concentrations of neuron-specific enolase and NR2 antibodies were identified among infants with and without a subsequent diagnosis of neurodevelopmental disorders (p>0.05).. The association between depressed endothelial nitric oxide synthase activation and insufficient endothelin-1 synthesis in the early days of life of very-low-birth-weight infants might be one of the causes of more serious and irreversible injury of brain tissue.

Topics: Azerbaijan; Cerebral Palsy; Developmental Disabilities; Endothelin-1; Female; Fetal Hypoxia; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Nitric Oxide; Nitric Oxide Synthase Type III