Impact of Hypoxia-Ischemia on Neurogenesis and Structural and Functional Outcomes in a Mild–Moderate Neonatal Hypoxia-Ischemia Brain Injury Model

Abstract

Hypoxic-ischemic encephalopathy (HIE) is a common type of brain injury caused by a lack of oxygen and blood flow to the brain during the perinatal period. The incidence of HIE is approximately 2–3 cases per 1000 live births in high-income settings; while in low- and middle-income countries, the incidence is 3–10-fold higher. Therapeutic hypothermia (TH) is the current standard treatment for neonates affected by moderate–severe HIE. However, more than 50% of all infants with suspected HIE have mild encephalopathy, and these infants are not treated with TH because of their lower risk of adverse outcomes. Despite this, several analyses of pooled data provide increasing evidence that infants who initially have mild encephalopathy may present signs of more significant brain injury later in life. The purpose of this study was to expand our knowledge about the effect of mild–moderate hypoxia-ischemia (HI) at the cellular, structural, and functional levels. An established rat model of mild–moderate HI was used, where postnatal day (P) 7 rats were exposed to unilateral permanent occlusion of the left carotid artery and 90 min of 8% hypoxia, followed by TH or normothermia (NT) treatment. The extent of injury was assessed using histology (P14 and P42) and MRI (P11 and P32), as well as with short-term and long-term behavioral tests. Neurogenesis was assessed by BrdU staining. We showed that mild–moderate HI leads to a progressive loss of brain tissue, pathological changes in MRI scans, as well as an impairment of long-term motor function. At P14, the median area loss assessed by histology for HI animals was 20% (p < 0.05), corresponding to mild–moderate brain injury, increasing to 55% (p < 0.05) at P42. The data assessed by MRI corroborated our results. HI led to a decrease in neurogenesis, especially in the hippocampus and the lateral ventricle at early time points, with a delayed partial recovery. TH was not neuroprotective at early time points following mild–moderate HI, but prevented the increase in brain damage over time. Additionally, rats treated with TH showed better long-term motor function. Altogether, our results bring more light to the understanding of pathophysiology following mild-moderate HI. We showed that, in the context of mild-moderate HI, TH failed to be significantly neuroprotective. However, animals treated with TH showed a significant improvement in motor, but not cognitive long-term function. These results are in line with what is observed in some cases where neonates with mild HIE are at risk of neurodevelopmental deficits in infancy or childhood. Whether TH should be used as a preventive treatment to reduce adverse outcomes in mild-HIE remains of active interest, and more research has to be carried out in order to address this question.

Comparing the efficacy in reducing brain injury of different neuroprotective agents following neonatal hypoxia–ischemia in newborn rats: a multi-drug randomized controlled screening trial

“…However, compared to the pooled HI/saline control, we found a significant neuroprotective treatment effect with a probability of efficacy of more than 97%. As explained in the statistical methods, this difference can be explained by the individual variability of treatment efficacy in the original experiment compared to the widespread variability of the pooled HI/saline group 20 , 53 , 54 .…”

“…We show here that Iodide at a concentration of 3 mg/kg administrated after ligation followed by two more maintenance doses every 24 h (Table 1 ) is neuroprotective following our well-established HI brain injury model, when compared against the pooled HI/saline group, with a probability of efficacy of 98.0%, whilst it was not considered neuroprotective when compared to the matched control group. Again, as explained in the statistical methods this difference can be explained by the individual variability of treatment efficacy in the original experiment compared to the widespread variability of the pooled HI/saline group 20 , 53 , 54 . Further experimental studies are needed to investigate the neuroprotective potency of Iodide.…”

GluN2B-containing NMDA receptor attenuated neuronal apoptosis in the mouse model of HIBD through inhibiting endoplasmic reticulum stress-activated PERK/eIF2α signaling pathway

“…The absence of reliable indicators to reflect the prognosis after the end of the 72-h continuous treatment is also an urgent problem to be solved ( Garcia-Alix et al, 2023 ). The lack of good therapeutic effects in mild HIBD patients ( Ehlting et al, 2022 ), differences in treatment effects between male and female rats ( Saadat et al, 2023 ), and other instabilities are driving research into the pathogenesis of HIBD, with the hope of proposing new targets to supplement and compensate for the shortcomings of hypothermia therapy. Our study elucidates that GluN2B plays a neuroprotective role in early development by inhibiting excessive activation of the PERK/eIF2α pathway.…”

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

“…The GO analysis indicated that the downregulated DEGs were mainly associated with biological processes related to nervous system development, neuron generation, and neurogenesis. Increasing evidence has demonstrated that the disruption of neurogenesis in the hippocampus significantly contributes to the development of cognitive impairment following neonatal HIBD 35,36 . The activation of the BDNF/TrkB signaling pathway plays a crucial role in reducing cell death in the vicinity of lesions, repairing neuronal damage, and facilitating neurogenesis 37 .…”

“…Increasing evidence has demonstrated that the disruption of neurogenesis in the hippocampus significantly contributes to the development of cognitive impairment following neonatal HIBD. 35 , 36 The activation of the BDNF/TrkB signaling pathway plays a crucial role in reducing cell death in the vicinity of lesions, repairing neuronal damage, and facilitating neurogenesis. 37 To identify a potential therapeutic target for treating neonatal HIBD, we investigated the neuroprotective effects of DEX on neurogenesis in the hippocampus through the BDNF/TrkB pathway.…”