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

Abstract

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.

Dr Cerebrolysin Improves Motor Abilities and Reverses the Long-Term Memory Acquisition Deficit in Rats with Hypoxic-Ischemic Encephalopathy

“…Besides, we found that HIE retarded growth development at PD60, which was not recoverable with Cerebrolysin treatment compared with the control group (Figure 2C). These results agree with other reports on growth deficits after HIE in rat pups at PD3 under 90-min hypoxia and in ischemic stroke models in adult rats where Cerebrolysin did not affect weight loss 18,32,34 . Also, the Cerebrolysin treatment did not affect the eye-opening age compared with the control groups (Figure 2D).…”

Effects of Cannabidiol, Hypothermia, and Their Combination in Newborn Rats with Hypoxic-Ischemic Encephalopathy

“…Hypoxia-ischemia led to memory deficits in both sensorimotor tests, as indicated by a 30% reduction in preference for new objects, as well as a 10% increase of preference for ipsilateral forepaw in the VEH group, which are similar to other studies ( Simola et al, 2008 ; Lee et al, 2010 ; Pazos et al, 2012 ; Duran-Carabali et al, 2019 ). This deficit may be explained by extensive damage in the hippocampus and cerebral cortex.…”

Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia

“…LPS) [78,79], since inflammation is thought to be a major cause of brain injury in preterm infants [80,81]. The pattern of brain lesion overlaps to a certain extent with that of the P7 model, for instance alteration in cortical development and myelination can be observed, albeit with subtle differences in neuronal populations affected, and short as well as long-term sensorimotor, motor and cognitive defects are also observed [82][83][84][85]. Nevertheless, contrary to the HI-P7 model, the hippocampus is typically spared in neonates exposed to HI before P7 [71].…”