Research progress of neonatal hypoxic-ischemic encephalopathy in nonhuman primate models

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the important complications of neonatal asphyxia, which not only leads to neurological disability but also seriously threatens the life of neonates. Over the years, animal models of HIE have been a research hotspot to find ways to cope with HIE and thereby reduce the risk of neonatal death or disability in moderate-to-severe HIE. By reviewing the literature related to HIE over the years, it was found that nonhuman primates share a high degree of homology with human gross neural anatomy. The basic data on nonhuman primates are not yet complete, so it is urgent to mine and develop new nonhuman primate model data. In recent years, the research on nonhuman primate HIE models has been gradually enriched and the content is more novel. Therefore, the purpose of this review is to further summarize the methods for establishing the nonhuman primate HIE model and to better elucidate the relevance of the nonhuman primate model to humans by observing the behavioral manifestations, neuropathology, and a series of biomarkers of HIE in primates HIE. Finally, the most popular and desirable treatments studied in nonhuman primate models in the past 5 years are summarized.

Keywords: biomarkers; ischemic and hypoxic encephalopathy; nonhuman primate; pathology; treatment.

Figure 1

Preparation of acute total asphyxia model: It is formed by placing a thin, saline‐filled rubber bladder on the head of a full‐term nonhuman primate fetus during surgical delivery while clamping the umbilical cord. The wrapping of the fetal head prevents the initiation of breathing, and the clamping of the umbilical cord hinders the circulation of the placental blood between the fetus and the mother. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Preparation of prolonged partial asphyxia: ① An overdose of oxytocin is injected into the maternal blood. ② Excess oxytocin stimulates the mother to experience frequent, intense uterine contractions and drastic vasoconstriction. ③ Maternal vasoconstriction reduces blood flow to the uterus, thereby reducing maternal blood flow across the placenta. ④ Delayed perfusion of the placental intervillous space significantly reduced the net exchange of respiratory gases between the mother and fetus, resulting in a significant decrease in the oxygen content of the fetal blood. ⑤ This eventually leads to hypoxic‐ischemic brain damage in neonates. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Production and delivery of erythropoietin (EPO): Hypoxia induces factor 1 (HIF‐1)‐triggered EPO gene expression, liver, and kidney secretion of EPO, and brain secretion of EPO, and upregulation of EPOR expression in the CNS. Brain damage caused by hypoxia increases the permeability of the blood–brain barrier (BBB), and EPO is more likely to cross the BBB and enter the brain to play its role. [Color figure can be viewed at wileyonlinelibrary.com]