The myth of the immature barrier systems in the developing brain: role in perinatal brain injury

Abstract

Central nervous system homeostasis is maintained by cellular barriers that protect the brain from external environmental changes and protect the CNS from harmful molecules and pathogens in the blood. Historically, for many years these barriers were thought of as immature, with limited functions, during brain development. In this review, we will present advances in the understanding of the barrier systems during development and evidence to show that in fact the barriers serve many important neurodevelopmental functions and that fetal and newborn brains are well protected. We will also discuss how ischaemic injury or systemic inflammation may breach the integrity of the barriers in the developing brain.

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

“…ROS lead to nuclear translocation of the transcription factor nuclear factor-kappa B (NF-κB) subunit p65, overexpressing the pro-inflammatory cytokines IL-1β and TNF-α, leading to glial reactivity and cell death [ 25 ]. Microglia and astrocytes are the cells firstly activated by PA, as evidenced by morphological changes, migration to damaged regions, and release of: (i) pro-inflammatory cytokines, TNF-α, IL1-β, and IL-6; (ii) glutamate; (iii) nitric oxide, and (iv) additional free radicals [ 26 , 27 , 28 ], contributing to a harmful cellular environment, causing neuronal and glial death [ 29 , 30 ]. Microglial infiltration, astrogliosis and upregulation of TNF-α and IL-1β have been observed 24 h and up to 2 months after birth in white and grey matter of post-mortem brains of infants suffering from hypoxic-ischemic encephalopathy [ 31 , 32 ].…”

The Neurovascular Unit: Effects of Brain Insults During the Perinatal Period

“…As discussed, Saunders et al (2012) made note of the commonly held, though largely unfounded, belief that the BBB within the developing brain was "immature" and lacked full functionality. Mallard et al (2018) have devoted a review to challenging this belief even further, highlighting a variety of neurodevelopmental functions contributed to by the BBB and other barrier mechanisms in fetal and newborn brains. One recent investigation has identified that BBB function is established prior to birth, although at different developmental points for different brain areas (Ben-Zvi et al, 2014).…”

Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key

“…Despite differences in etiology (infectious versus sterile inflammation), cross-talk between the peripheral immune system and the immune-privileged brain parenchyma is central in the pathophysiology of preterm brain injury. The biochemical cascade initiated after HI and antenatal infection results in the release of danger-associated molecular patterns (DAMPs) and cytokines (IL-6 in particular) from the circulation contribute to the activation of cerebral endothelium and disruption of the blood-brain barrier, as elegantly reviewed by Mallard et al [ 85 ], thereby undermining central nervous system (CNS) immune privilege and allowing active recruitment of leukocytes that contribute to the neuroinflammatory response, which is primarily mediated by microglia [ 63 , 86 , 87 ].…”