Tissue Injury and Astrocytic Reaction, But Not Cognitive Deficits, Are Dependent on Hypoxia Duration in Very Immature Rats Undergoing Neonatal Hypoxia-Ischemia.

Preterm birth and hypoxia-ischemia (HI) are major causes of neonatal death and neurological disabilities in newborns. The widely used preclinical HI model combines carotid occlusion with hypoxia exposure; however, the relationship between different hypoxia exposure periods with brain tissue loss, astrocyte reactivity and behavioral impairments following HI is lacking. Present study evaluated HI-induced behavioral and morphological consequences in rats exposed to different periods of hypoxia at postnatal day 3. Wistar rats of both sexes were assigned into four groups: control group, HI-120 min, HI-180 min and HI-210 min. Neurodevelopmental reflexes, exploratory abilities and cognitive function were assessed. At adulthood, tissue damage and reactive astrogliosis were measured. Animals exposed to HI-180 and HI-210 min had delayed neurodevelopmental reflexes compared to control group. Histological assessment showed tissue loss that was restricted to the ipsilateral hemisphere in lower periods of hypoxia exposure (120 and 180 min) but affected both hemispheres when 210 min was used. Reactive astrogliosis was increased only after 210 min of hypoxia. Interestingly, cognitive deficits were induced regardless the duration of hypoxia and there were correlations between behavioral parameters and cortex, hippocampus and corpus callosum volumes. These results show the duration of hypoxia has a close relationship with astrocytic response and tissue damage progression. Furthermore, the long-lasting cognitive memory deficit and its association with brain structures beyond the hippocampus suggests that complex anatomical changes should be involved in functional alterations taking place as hypoxia duration is increased, even when the cognitive impairment limit is achieved.

Prenatal and Early Postnatal Environmental Enrichment Reduce Acute Cell Death and Prevent Neurodevelopment and Memory Impairments in Rats Submitted to Neonatal Hypoxia Ischemia.

Environmental enrichment (EE) is an experimental strategy to attenuate the negative effects of different neurological conditions including neonatal hypoxia ischemia encephalopathy (HIE). The aim of the present study was to investigate the influence of prenatal and early postnatal EE in animals submitted to neonatal HIE model at postnatal day (PND) 3. Wistar rats were housed in EE or standard conditions (SC) during pregnancy and lactation periods. Pups of both sexes were assigned to one of four experimental groups, considering the early environmental conditions and the injury: SC-Sham, SC-HIE, EE-sham, and EE-HIE. The offspring were euthanized at two different time points: 48 h after HIE for biochemical analyses or at PND 67 for histological analyses. Behavioral tests were performed at PND 7, 14, 21, and 60. Offspring from EE mothers had better performance in neurodevelopmental and spatial memory tests when compared to the SC groups. HIE animals showed a reduction of IGF-1 and VEGF in the parietal cortex, but no differences in BDNF and TrkB levels were found. EE-HIE animals showed reduction in cell death, lower astrocyte reactivity, and an increase in AKTp levels in the hippocampus and parietal cortex. In addition, the EE was also able to prevent the hippocampus tissue loss. Altogether, present findings point to the protective potential of the prenatal and early postnatal EE in attenuating molecular and histological damage, as well as the neurodevelopmental impairments and the cognitive deficit, caused by HIE insult at PND 3.