Mechanisms of perinatal arterial ischemic stroke

Abstract

The incidence of perinatal stroke is high, similar to that in the elderly, and produces a significant morbidity and severe long-term neurologic and cognitive deficits, including cerebral palsy, epilepsy, neuropsychological impairments, and behavioral disorders. Emerging clinical data and data from experimental models of cerebral ischemia in neonatal rodents have shown that the pathophysiology of perinatal brain damage is multifactorial. These studies have revealed that, far from just being a smaller version of the adult brain, the neonatal brain is unique with a very particular and age-dependent responsiveness to hypoxia-ischemia and focal arterial stroke. In this review, we discuss fundamental clinical aspects of perinatal stroke as well as some of the most recent and relevant findings regarding the susceptibility of specific brain cell populations to injury, the dynamics and the mechanisms of neuronal cell death in injured neonates, the responses of neonatal blood-brain barrier to stroke in relation to systemic and local inflammation, and the long-term effects of stroke on angiogenesis and neurogenesis. Finally, we address translational strategies currently being considered for neonatal stroke as well as treatments that might effectively enhance repair later after injury.

Figure 1

Magnetic resonance imaging (MRI)-based delineation of the ischemic core and penumbra. (A, B) Diffusion-weighted MRI (DWI) in human term babies 3 to 5 days after arterial ischemic stroke delineates the presence of penumbra (in red). Core and penumbra can be determined using a computational analysis method (Hierarchical Region Splitting) based on apparent diffusion coefficient threshold values as described in Ashwal et al. The axis in (B) denotes data from six individual term neonates showing total lesion, core, and penumbral volumes. Note the wide variability in volumes that can occur in neonatal arterial ischemic stroke (AIS). (C) An example of injury volumes in a rat pup model of AIS. The 3D volume of ‘tissue at risk' corresponds to the increasing duration of transient middle cerebral artery occlusion in the postnatal day 10 (P10) rats. Note the increasing size of the ischemic core (yellow) and penumbra (gray) in the hemisphere ipsilateral to the occlusion (courtesy of Stephen Ashwal and Andy Abenous, Department of Pediatrics, Lomo Linda University). These types of translational studies may provide better data regarding injury severity that could be applied to future clinical trials.

Figure 2

Depletion of microglial cells before a transient 3 hour middle cerebral artery occlusion (MCAO) in postnatal day 7 (P7) rats does not reduce the levels of several cytokines and chemokines elevated by injury induction. (A) While IbaI⁺ microglia are abundant in the penumbra 24 hours after injury in pups treated with phosphate buffered saline (PBS)-liposomes, essentially no IbaI⁺ microglia are seen in pups after intracerebral injection of liposome-encapsulated clodronate (Clod-liposomes). (B) Concentrations of cytokines and chemokines in injured (Ipsi) and contralateral (Contra) hemispheres. Note that only the levels of interleukin 18 (IL-18) are significantly reduced by depletion of microglial cells. *P<0.05.

Figure 3

Stroke induces rapid nonoverlapping changes in gene expression in endothelial cells within injured regions in adults and neonates. Heatmaps obtained in endothelial cells isolated from injured adult and neonatal brains 24 hours after transient 3 hours MCAO, as described in Fernandez et al. Heatmap visualization from a total of 31,042 probe sets shows that the expression levels of endothelial genes are markedly changed in injured regions compared with the corresponding contralateral anatomic regions in the same rats in each age group but that the patterns of changes are distinct after adult and neonatal stroke. The expression levels of genes are indexed by color.

Figure 4

A schematic diagram that shows major differences in the response of the blood–brain barrier to acute stroke between adults and neonates. (A) Under normal conditions the peripheral and local brain compartments are separated by fine-tuned cell–cell interactions at the neurovascular interface. After stroke, direct damage to several cell types, in concert with activation of immune cells and altered cell–cell communications, adversely affect functional integrity of the blood–brain barrier (BBB). Boxes point to known differences in processes in cerebral cortical regions affected by transient middle cerebral artery occlusion (tMCAO) in adult and neonatal rodents. BM/ECM, basal membrane/extracellular matrix. (B) Events at the neurovascular interface after tMCAO in neonatal rats: 1—peripheral cytokines and chemokines activate leukocytes and prime endothelium; 2—extravasation of neutrophils and monocytes is low, contributing to functional preservation of the BBB. Note that in adult rats after tMCAO leukocytes extravasate into ischemic-reperfused brain regions through distorted BBB; 3—BBB leakage is low compared with major BBB leakage and associated entrance of variety of molecules from peripheral circulation entering the injured adult brain; 4—inflammatory mediators that either enter the brain or are produced by local cells activate resident brain cells, including further activation of microglia, macrophages, endothelial cells, and astrocytes; 5—microglial cells signal to neurons; 6—processes shown as 1 to 3 activate microglial cells, prompting morphologic and functional transformation of these cells to brain macrophages. Peripheral monocytes that enter the brain gradually differentiate to become brain macrophages, but activated microglial cells are the predominant population of brain macrophages after acute injury; 7—activated microglia/macrophages directly signal to neurons; 8—microglia/macrophages produce various cytokines and chemokines; and 9—astrocytes directly communicate with neurons and cells of the neurovascular units. 4 to 9—compared with injury in the adult brain, cell–cell communications differ in the newborn in at least several respects, as described in the text.