Destruction and reconstruction: Hypoxia and the developing brain

Abstract

Preterm infants have a high rate of neurodevelopmental handicap. Recent imaging studies have revealed that adverse outcomes are strongly associated with reduced brain growth and neural complexity in later life. Increasing data suggest that these chronic deficits primarily reflect acute neuronal and glial injury sustained during adverse in utero events, such as exposure to severe hypoxia-ischemia and inflammation. In the present review we examine recent evidence that this chronic impairment is partly due to upregulation of physiological apoptosis, related to input deprivation, and output isolation secondary to acute white and gray matter damage and axonal injury. However, progenitor cells in the subventricular zone (SVZ) are also vulnerable to injury, and loss of part of this critical population likely further compromises brain development. Based on these concepts the impact of proposed interventions such as induced hypothermia and endogenous growth factors are likely to be complex, but potentially offer focused ways of improving the outcomes of premature birth.

Strain Differences in Behavioral and Cellular Responses to Perinatal Hypoxia and Relationships to Neural Stem Cell Survival and Self-Renewal

“…12 Pups used for tissue analyses of SVZ NSC survival proliferation 14 were sacrificed at P11 (approximates a full-term gestation in humans). 15,16 Mice to be used for behavioral analysis were exposed in the same manner between P3 and P11 and were then kept under normoxic conditions from P12 until the completion of testing.…”

“…14 At P3 (approximates a 23-week gestational age in humans), 15,16 cohorts of mothers and pups were subjected to hypoxic (10% O 2 ) treatment; control mice remained under normoxic conditions as described. 12 Pups used for tissue analyses of SVZ NSC survival proliferation 14 were sacrificed at P11 (approximates a full-term gestation in humans).…”

Evaluation of apoptotic cell death following transient maternal hypotension in fetal rat brain: temporal pattern within the first 24 h after procedure

“…Our results demonstrated apoptosis around lateral ventricular walls as early as 0 and 6 h after hypotension, reaching the highest degree at 12 h, and declining between 12 and 24 h. In accordance with our results, the subventricular zone (SVZ) is reported among the regions vulnerable to prenatal injury. In the study by Romanko et al, activated calpains and caspase-3 colocalized in the lateral SVZ, an area rich in progenitor cells, but not in the medial SVZ; this type of injury may alter brain development and create long-term and more widespread effects (28,33). The activation of caspase-3 may be more extensive in HI-induced neuronal death in immature neurons compared to mature neurons (17,19) and susceptibility of neurons to injuries varies with age (17).…”

Asphyxia and Therapeutic Hypothermia Modulate Plasma Nitrite Concentrations and Carotid Vascular Resistance in Preterm Fetal Sheep

“…1,2 In term infants, mild induced hypothermia improves survival without disability after moderate to severe hypoxiaischemia at 18 months of age. 3 There is now preclinical evidence that induced hypothermia after asphyxia is neuroprotective in preterm fetal sheep, 4,5 but there are no data on preterm infants because of historical concerns about potential adverse effects, such as intracranial hemorrhage, during cooling in preterm infants.…”