Cerebral ischemia in the developing brain

Abstract

Brain ischemia affects all ages, from neonates to the elderly population, and is a leading cause of mortality and morbidity. Multiple preclinical rodent models involving different ages have been developed to investigate the effect of ischemia during different times of key brain maturation events. Traditional models of developmental brain ischemia have focused on rodents at postnatal day 7-10, though emerging models in juvenile rodents (postnatal days 17-25) indicate that there may be fundamental differences in neuronal injury and functional outcomes following focal or global cerebral ischemia at different developmental ages, as well as in adults. Here, we consider the timing of injury in terms of excitation/inhibition balance, oxidative stress, inflammatory responses, blood brain barrier integrity, and white matter injury. Finally, we review translational strategies to improve function after ischemic brain injury, including new ideas regarding neurorestoration, or neural repair strategies that restore plasticity, at delayed time points after ischemia.

Keywords: Juvenile; global cerebral ischemia; neonatal ischemia; neurodevelopment; neurorestoration; pediatric stroke.

Figure 1.

Mechanisms leading to increased sensitivity to oxidative stress in the neonatal brain following cerebral ischemia. The neonatal brain may be at increased risk of oxidative injury due to high concentrations of unsaturated fatty acids, hyperoxygenation with reperfusion and decreased cellular oxygen consumption (leading to increased oxygen ions), as well as a developmental lag in the expression of superoxide dismutase and low expression and activity of H₂O₂-utilizing enzymes glutathione peroxidase and NADPH oxidase. These developmental changes lead to increased ROS accumulation and make the neonatal brain vulnerable to oxidative injury after cerebral ischemia.

Figure 2.

Relative age-related role of inflammatory components following stroke. Following stroke in the adult brain (blue line), infiltration of neutrophils, lymphocytes, microglia and monocytes contribute to neuronal injury and death. Many of these same factors contribute to neuronal injury in the juvenile brain (red line), though infiltration of T lymphocytes has not been established. Following neonatal stroke (orange line), resident microglial activation contributes to ischemic neuronal injury and death, but infiltration of neutrophils and monocytes are not involved in the pathogenic cascade. γδT-cells contribute to acute neuronal cell death following neonatal H-I, whereas CD4⁺ and CD8⁺ T-cells contribute to chronic inflammatory changes in the neonatal brain following ischemia.

Figure 3.

Age-related differences in the blood brain barrier (BBB). Compared to the compromised BBB after ischemia in the adult brain, the BBB in the neonate is less permeable (varying by BBB permeability assay, see text for more detail) following ischemia. This is likely due to the relative increase in tight junction and basal lamina proteins occludin, claudin, and laminin in the neonatal brain. The result is increased infiltration of inflammatory cells, large proteins, and edema in the adult brain, whereas only small molecules such as sucrose cross the BBB into the neonatal brain. This likely has implications for the available delivery of therapeutics into the neonatal brain via the vasculature following cerebral ischemia.

Figure 4.

Age, cellular maturation, and ischemia-induced changes in oligodendrocytes. Both Panels: OPC’s have greater expression of AMPA GluR’s and decreased anti-oxidant proteins and enzymes compared to more mature oligodendrocytes. As oligodendrocytes mature, antioxidant capacity increases due to increased expression of glutathione pathway enzymes. However, there are age-related differences in oligodendrocytes at similar cellular maturational stages. FGF and IGF induce late OPCs from neonatal brains to revert to a less mature state and proliferate (top panel), while late OPCs from adult rodent brains are more likely to differentiate under the same conditions (bottom panel). Immature OL’s in juvenile mice express more GSTπ (top panel) relative to immature OL’s in adult mice (bottom panel). In response to ischemia, late OPCs are selectively vulnerable to cell death, there is rapid proliferation of less mature OPCs (top panel). However, there is maturational arrest of OPCs, limiting remyelination (top panel). In the adult brain, immature and mature OL’s are relatively more vulnerable to ischemia (bottom panel).