The biological basis of injury and neuroprotection in the fetal and neonatal brain

Abstract

A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.

Prenatal growth in humans and postnatal brain maturation into late adolescence

“…Exquisite sensitivity of the developing brain to prenatal environmental insults has been well established through experimental animal models (1). In humans, where experimental approaches are not feasible, numerous observational studies have linked frank insults during prenatal life [as indexed by premature delivery (2); abnormally low birth weight for gestational age (3); and maternal exposure to radiation (4) or starvation (5)], to altered postnatal brain development.…”

Epigenetic regulation of fetal brain development and neurocognitive outcome

“…In this primate model, modest energy restriction in mothers during their pregnancies alters the balance between rates of cell birth and cell death by apoptosis in the subventricular zone during the midgestational period and reduces the density of the subplate neuronal network. It is not clear just how the near-optimal placental supply of nutrients, as inferred in the present human twin study (3), affects cortical development at the molecular level, but it is assumed that the differences between the twins are not a consequence of cellular damage, which is the case in severe hypoxia and other pathological conditions (2). Most likely, the mechanisms include epigenetic changes, such as alterations in methylation Even the subtle normal variations of intrauterine environment may lead to recognizable differences in postnatal brain structure and cognitive functions.…”

“…Since that time, it has been well-established that hypoxia, infection, and other noxious factors can cause fetal brain injury and intrauterine growth restriction and that prenatal brain lesions can cause alterations in the postnatal brain development (2). A study in PNAS (3) suggests that even the subtle normal variations of intrauterine environment may lead to recognizable differences in postnatal brain structure and cognitive functions.…”

“…It is not surprising to find positive correlation with postnatal neurocognitive outcome in cases of extreme birth weight variation (below the 10th percentile), because placental transfer in such cases is shifted to a pathological level (2). However, it is not expected that neurocognitive maturation during late adolescence would depend on relatively small differences in the supply of nutrients that fall at the low end of the normal range (near-optimal environment).…”

“…Mechanisms regulating fetal growth and potentially causing birth weight variations are already operative during the second trimester of gestation, because the placenta is well-developed by this stage (2,5). According to the work by Raznahan et al (3), the most likely areas of the brain that are affected are high-order associative regions, especially subventricular proliferating precursor cells of neurons destined to project to other cortical regions and the emerging corticocortical pathways through subplate.…”