Brain Maturation as a Fundamental Factor in Immune-Neurovascular Interactions in Stroke

Abstract

Injuries in the developing brain cause significant long-term neurological deficits. Emerging clinical and preclinical data have demonstrated that the pathophysiology of neonatal and childhood stroke share similar mechanisms that regulate brain damage, but also have distinct molecular signatures and cellular pathways. The focus of this review is on two different diseases-neonatal and childhood stroke-with emphasis on similarities and distinctions identified thus far in rodent models of these diseases. This includes the susceptibility of distinct cell types to brain injury with particular emphasis on the role of resident and peripheral immune populations in modulating stroke outcome. Furthermore, we discuss some of the most recent and relevant findings in relation to the immune-neurovascular crosstalk and how the influence of inflammatory mediators is dependent on specific brain maturation stages. Finally, we comment on the current state of treatments geared toward inducing neuroprotection and promoting brain repair after injury and highlight that future prophylactic and therapeutic strategies for stroke should be age-specific and consider gender differences in order to achieve optimal translational success.

Keywords: Blood–brain barrier; Childhood arterial stroke; Choroid plexus; Inflammation; Neonatal stroke.

Fig. 1

Schematic representation of the development of individual cell types and of the maturing neurovascular unit during embryonic and postnatal brain development in rodents. Vertical punctate lines indicate approximate time for inducing tMCAO to mimic PAIS, CAIS, and AIS. As is evident from this cartoon presentation, physiological neuronal apoptosis (i.e., programmed cell death) is high in the newborn brain and rapidly declines during perinatal period. Microglial function undergoes changes with development. Peripheral cells are immature in neonatal mice and reach maturation during juvenile period. The BBB is established by birth but continues to change in neonatal and juvenile brain. Astrocyte and pericyte coverage continues to increase in neonatal and juvenile brain. Myelination begins during postnatal period and is complete in juvenile rodents. Image created with BioRender.com

Fig. 2

Developmental changes in expression of individual TJ proteins during postnatal days P9–P60. On Y axes, 1 represents expression of individual proteins in P7 rat brain based on Western Blot data published in [108]

Fig. 3

Examples of effects of 3h MCAO followed by 24h reperfusion in P7 rats on the ECM degradation (A), vascular Aqp-4 coverage (B), and BBB integrity (C). A In situ zymography in coronal section (right) shows ECM degradation in the penumbral and ischemic core regions, regions defined by Nissl staining (left). B Aqp-4 coverage of vessels in contralateral region (top) and ischemic-reperfused region (bottom). Note that Aqp-4 expression is reduced and detracted from the vessels in ischemic-reperfused region. C 70-kDa Dextran administered 23 h after reperfusion is observed within vessels in both contralateral (image on the left) and the injured cortex (image on the right)

Fig. 4

Brain maturation–dependent differences in individual mechanisms of acute injury in rodent models of PAIS, CAIS, and AIS