Magnetic Resonance Imaging Findings of Term and Preterm Hypoxic-Ischemic Encephalopathy: A Review of Relevant Animal Models and Correlation to Human Imaging

Jisa, Kyle A.; Clarey, Dillon; Peeples, Eric S.

doi:10.2174/1874440001812010055

Cited by 11 publications

(6 citation statements)

References 65 publications

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“…Additionally, neuroprotection was associated with induction of immunosuppressive M2c-like microglia (cluster of differentiation 163; CD163 immunoreactive microglia) within the white matter and significant elevations in the systemic concentration of anti-inflammatory cytokines IFN-β and interleukin-10 (IL-10). However, HI brain injury can evolve over days and even weeks 22,23 . Indeed, evidence from several animal models of perinatal brain injury suggest cell death typically occurs during the secondary phase of injury, and is often followed by a chronic or tertiary phase of injury characterized by progressive cell death and remodeling 24,25 .…”

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confidence: 99%

Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

Cho

Zeng

Anekal

et al. 2020

Sci Rep

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In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1-4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.Preterm birth is closely associated with long-term neurodevelopmental disability 1 . While survival rates among preterm infants have significantly improved, rates of neonatal morbidity remain high with 50% of extremely preterm infants displaying cognitive and behavioural difficulties 2-4 . The etiology of preterm brain injury is multifactorial 5 , however a key contributing factor is the greater occurrence of acute hypoxic ischemic encephalopathy (HIE) in moderately preterm infants compared to term 6 . Therapeutic mild hypothermia is now standard care for term newborns after moderate to severe HIE 7 . Despite its benefits, mild hypothermia is not recommended for preterm infants <35 weeks gestational age 8,9 . Thus, there is a considerable unmet need for neuroprotective therapies for preterm infants with acute HIE.Growing evidence suggests that inflammation plays a critical role in the pathogenesis of HIE and immunomodulatory drugs have therapeutic promise 10 . Toll-like receptors (TLRs) are key regulators of the initial inflammatory response to HI, and while implicated in brain injury, they can be neuroprotective via tolerance (pre-conditioning) and immunomodulation 11 . The TLR7 signaling pathway can modulate both pro-and anti-inflammatory responses in central and peripheral immune cells 12-15 , with the potential to reduce inflammatory injury within the CNS [16][17][18] . We have previously shown that pre-conditioning with the inflammatory mediator lipopolysaccharide (LPS) ...

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Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

Cho

Zeng

Anekal

et al. 2020

Sci Rep

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“…One of the main advantages of this model is its flexibility in replicating both preterm (rodent postnatal days 1–6) and term (rodent postnatal days 7–10) human foetal injury ( Jisa et al, 2018 ).…”

Section: Animal Models Of Hypoxia–ischaemiamentioning

confidence: 99%

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

Tetorou

Sisa

Iqbal

et al. 2021

Front. Synaptic Neurosci.

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Neonatal hypoxic–ischaemic brain damage is a leading cause of child mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The majority of neonatal hypoxic–ischaemic cases arise as a result of impaired cerebral perfusion to the foetus attributed to uterine, placental, or umbilical cord compromise prior to or during delivery. Bacterial infection is a factor contributing to the damage and is recorded in more than half of preterm births. Exposure to infection exacerbates neuronal hypoxic–ischaemic damage thus leading to a phenomenon called infection-sensitised hypoxic–ischaemic brain injury. Models of neonatal hypoxia–ischaemia (HI) have been developed in different animals. Both human and animal studies show that the developmental stage and the severity of the HI insult affect the selective regional vulnerability of the brain to damage, as well as the subsequent clinical manifestations. Therapeutic hypothermia (TH) is the only clinically approved treatment for neonatal HI. However, the number of HI infants needed to treat with TH for one to be saved from death or disability at age of 18–22 months, is approximately 6–7, which highlights the need for additional or alternative treatments to replace TH or increase its efficiency. In this review we discuss the mechanisms of HI injury to the immature brain and the new experimental treatments studied for neonatal HI and infection-sensitised neonatal HI.

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“…Preterm birth frequently affects the white matter integrity of the brain that underlies executive functioning, in particular in the prefrontal region, thalamus, and basal ganglia [ 12 , 13 ]. Contributing factors seem to be a disrupted process of myelination in preterm borns [ 13 ], and ischemic-hypoxic events that occur more frequently among preterm borns [ 7 , 14 ]. Poorer executive functioning may underlie the academic problems and the emotional and behavioral problems at a later age of MLPs [ 12 ].…”

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confidence: 99%

Stability of Executive Functioning of Moderately-Late Preterm and Full-Term Born Children at Ages 11 and 19: The TRAILS Cohort Study

Reijneveld

Hornman

Boelema

et al. 2021

IJERPH

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Moderately-late preterm-born children (MLPs, 32–36 weeks gestational age, GA) have poorer executive functioning (EF) at primary school age than full-term children (FTs). Evidence is lacking on their EF in adolescence, but for early preterm-born children, this has been shown to be much poorer. We, therefore, compared EF of MLPs and FTs at ages 11 and 19 and assessed development between these ages. We obtained data from TRAILS, a community-based prospective cohort study in the northern Netherlands, on 98 MLPs and 1832 FTs. We assessed EF by the Amsterdam Neuropsychological Tasks (ANT) at ages 11 and 19 years and computed gender-specific z-scores on reaction time and accuracy. We compared baseline speed, pattern search, working memory, sustained attention, inhibition, and attentional flexibility of MLPs and FTs crude, and adjusted for small-for-GA status, socioeconomic status, and estimated intelligence. MLPs and FTs performed similarly on all EF components at ages 11 and 19, except for the speed, but not the accuracy measure of attentional flexibility. This was slightly poorer for MLPs than FTs at age 19 (adjusted B 0.25; 95% confidence interval: 0.00 to 0.50; p = 0.047), but not at age 11 (adjusted B −0.02; −0.19 to 0.22; p = 0.87). Differences in EF between MLPs and FTs did not change significantly from age 11 to 19. MLPs had comparable EF on most components as FTs, with only attentional flexibility at age 19 developing slightly poorer for MLPs than for FTs. These findings suggest the effects of MLP birth on long-term EF to be small.

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Magnetic Resonance Imaging Findings of Term and Preterm Hypoxic-Ischemic Encephalopathy: A Review of Relevant Animal Models and Correlation to Human Imaging

Cited by 11 publications

References 65 publications

Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

Effects of delayed intraventricular TLR7 agonist administration on long-term neurological outcome following asphyxia in the preterm fetal sheep

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

Stability of Executive Functioning of Moderately-Late Preterm and Full-Term Born Children at Ages 11 and 19: The TRAILS Cohort Study

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