Resumen de Brain reorganization in an experimental model of intrauterine growth restriction

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• 1.- INTRODUCTION Intrauterine growth restriction (IUGR) due to placental insufficiency affects 5-10% of all pregnancies. This condition is a risk factor for brain damage after birth and cognitive disorders later in childhood. The pathophysiological pathways leading to adverse neurodevelopmental outcome remain poorly understood. The use of animal models is essential to advance in the understanding of brain injury in IUGR. 2.- OBJECTIVE To develop a suitable experimental model of IUGR in fetal rabbits, in order to conduct a detailed description of the neurostructural brain abnormalities associated with this disease and their neurobehavioral correlates. 3.- MATERIAL AND METHODS P1: Comparison of two experimental models of IUGR: undernutrition versus selective ligature of uteroplacental vessels Prenatal induction of IUGR at 25D by means of a surgical protocol or hiponutirtion. Comparison of neonatal biometries, mortality and hemodynamic changes. P2: Evaluation of different timings and severity of the intervention Prenatal induction of IUGR at 21/25D by means of a surgical protocol (two proportion of ligature (20-30%(mild) or 40-50%(severe)). Comparison of neonatal biometries, mortality and histological brain changes. P3: Anatomical patterns of brain reorganization induced by IUGR and neurobehavioral correlates. Prenatal induction of IUGR at 25D by means of a surgical protocol. Comparison of neurobehaviour and diffusion related parameters obtained by MRI. 4.- RESULTS P1: Comparison of two experimental models of IUGR: undernutrition versus. selective ligature of uteroplacental vessels Fetal mortality rate in control and undernutrition did not show any difference. On the contrary, the ligature group showed a significantly higher mortality rate. (14.3 vs 5.0 vs 54.2%,p<0,001). Neonatal biometries decreased significantly across the experimental groups. Only ligature group showed significant changes in hemodynamic parameters when compared with control. P2: Efectes del moment i la severitat de la lligadura selectiva There was a linear increase in mortality rates across the experimental groups when ordered by gestational age and severity (Linear-by-linear p<0.001). Neonatal biometries showed a significant linear decrease across the experimental groups at 21D and 25D. Finally, markers of brain damage showed a regional patterns according to severity and onset of IUGR. P3: Anatomical patterns of brain reorganization induced by IUGR and neurobehavioral correlates. Growth restricted pups showed poorer results in all parameters. When VBA analysis was applied, statistically significant differences were found in FA distribution between cases and controls in multiple structures that were correlated with most of neurobehavioral domains. 5.- CONCLUSIONS Selective ligature of uteroplacental vessels in the pregnant rabbit reproduces more closely the features of human IUGR than models based on maternal undernutrition. The gestational age and the proportion of vessels ligated produces gradual changes in mortality and biometrical restriction and different patterns of histological changes in the fetal rabbit brain. Finally, IUGR results in a complex regional pattern of neurostructural differences that correlate with specific neurobehavioral changes in neonatal life.