The RV model was first described in postnatal day-seven (P7) rats, and the protocol consists of the unilateral permanent occlusion of the common carotid artery (CCA)-ischemia-followed by exposure to a variable period of reduced oxygen levels (usually 8%)-hypoxia. One of the most widely used animal models for the assessment of hypoxic-ischemic brain damage in the neonatal brain is the Rice–Vannucci (RV) murine model. The HI insult affects differently the preterm and term brain, originating different types of injury. ĭue to poor antioxidant defenses and higher fatty acid concentrations, the developing brain is more susceptible to oxidative stress, therefore being highly vulnerable to hypoxic-ischemic insults. Magnetic resonance imaging studies of term newborns diagnosed with HIE revealed characteristic patterns of brain injury that can relate to mechanisms, severity, and duration of the HI insult, such as the parasagittal cerebral injury pattern or watershed injury, involving cortical gray matter and subcortical white matter, which can be related with cerebral hypoperfusion and low sustained systemic blood pressure, and the selective neuronal necrosis pattern either involving basal ganglia and brain stem in severe acute events or in a diffuse global injury when severe but also prolonged HI events occur. Months after the HI insult, alterations caused by this injury are still occurring, namely late cell death, remodeling of the injured brain, astrogliosis, as well as epigenetic changes. Research shows that this type of injury comprises different stages: energy depletion, inflammation, excitotoxicity, oxidative stress, and apoptosis. This hypoxic-ischemic (HI) event can occur due to placental abruption, uterine rupture, and cord prolapse, among others. Neonatal HIE is originated from an insult that involves a period of reduced blood flow and oxygen delivery to the brain of neonates-ischemia and hypoxia, respectively. Infants diagnosed with HIE have a reserved prognosis since the HIE mortality rate is about 25%, and 20% of the survivors develop moderate to severe long-term impairment. In developed countries, neonatal HIE incidence is approximately 0.5 to 1 case per 1000 live births however, the global estimate is highly influenced by the higher incidence found in developing countries. The estimated incidence of HIE is variable across studies, ranging from 1 to 8 cases per 1000 live births. Ībout a quarter of neonatal deaths worldwide can be attributed to perinatal asphyxia. This condition also represents a major economic burden to the government and caretakers. The different outcomes of this condition can be severe, profoundly affecting the daily life of patients and their families. Several disorders are associated with HIE, namely epilepsy, cerebral palsy, attention deficit hyperactivity disorder, seizures, hearing and vision loss, language disorders, and cognitive delay.
Hypoxic-ischemic encephalopathy (HIE) is one of the major causes of neonatal death and long-term disability, leading to chronic motor and cognitive impairments. Nonetheless, few preclinical studies assessed the combination of TH and SCT for HIE, and the existent studies show some contradictory results, revealing the need to further explore this line of research. These results show the potential of SCT for HIE and the possibility of this therapy, in combination with TH, becoming the next therapeutic approach for HIE.
Outstandingly, about 80% of these studies reported a significant improvement of cognitive and/or sensorimotor function, as well as decreased brain damage. With this systematic review, we gathered information included in 58 preclinical studies from the last decade, focusing on the ones using stem cells isolated from the umbilical cord blood, umbilical cord tissue, placenta, and bone marrow. Addressing this concern, several preclinical studies assessed the potential of stem cell therapy (SCT) for HIE. Currently, therapeutic hypothermia (TH) is the standard of care in developing countries however, TH is not always effective, especially in severe cases of HIE. This condition results from a period of ischemia and hypoxia to the brain of neonates, leading to several disorders that profoundly affect the daily life of patients and their families.
Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in the perinatal period.
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