Review: Molecular pathogenesis of blood–brain barrier breakdown in acute brain injury

Abstract

Historically, the blood-brain barrier (BBB) was considered to be at the level of cerebral endothelium. Currently, the interaction of endothelium with other components of the vessel wall and with neurones and glial cells is considered to constitute a functional unit, termed the neurovascular unit that maintains cerebral homeostasis in steady states and brain injury. The emphasis of this review is on cerebral endothelium, the best-studied component of the neurovascular unit, and its permeability mechanisms in health and acute brain injury. Major advances have been made in unravelling the molecular structure of caveolae and tight junctions, both of which are components of the structural barrier to the entry of plasma proteins into brain. Time course studies suggest that caveolar changes precede junctional changes in acute brain injury. Additional factors modulating BBB permeability in acute brain injury are matrix metalloproteinases-2 and 9 and angiogenic factors, the most notable being vascular endothelial growth factor-A and angiopoietins (Ang) 1 and 2. Vascular endothelial growth factor-A and Ang2 have emerged as potent inducers of BBB breakdown while Ang1 is a potent anti-leakage factor. These factors have the potential to modulate permeability in acute brain injury and this is an area of ongoing research. Overall, a combination of haemodynamic, structural and molecular alterations affecting brain endothelium results in BBB breakdown in acute brain injury.

Identification and Dynamic Regulation of Tight Junction Protein Expression in Human Neural Stem Cells

“…The TJP complex is composed of transmembranous occludin, claudins, and junctional adhesion molecules that connect to the actin cytoskeleton through intermediary TJP accessory/anchoring proteins ZO-1, -2, and -3 [14][15][16]. TJ complexes are highly dynamic structures that respond quickly to intracellular signaling events and may experience rapid changes in the subcellular distribution of their composite proteins, as well as fluctuations in gene expression and various post-translational modifications [15,17,18].…”

F2-isoprostanes and F4-neuroprostanes as markers of intracranial aneurysm development

“…3 Brain susceptibility to oxidative stress results from the consumption of large amounts of oxygen, alteration of the blood-brain barrier and bio-activation of glial cells. 4 Moreover, the metabolism of the brain is characterized by the promotion of ROS due to its unique metabolic features, such as neurotransmitter oxidation. 5 Some glial cells and macrophages can produce the superoxide anion (O 2 -), nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ) indirectly through the cytokine activation.…”

Substance P: A Novel Target in the Treatment of Cerebral Oedema and Elevated Intracranial Pressure Following Traumatic Brain Injury

“…It is comprised of a complex network of cells that make up the cerebral capillaries and post-capillary venules, resting on the basal lamina [8]. The gate function of the BBB is provided by the tight and adherin junctions, composed of a complex network of transmembrane and cytosolic proteins [7].…”