Abstract
The blood–brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1–3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.
Highlights
The blood–brain barrier (BBB) is a dynamic physiological structure that constitutes an interface between the vasculature system and the neural tissues, regulating diverse processes such as cerebral blood flow and angiogenesis, neuronal development, and synaptic activity [1]
One rather complex condition is acute ischemic stroke (AIS). This pathology is characterized by different hemodynamic stages where BBB permeability (BBBP) can either be a friend or a foe, favoring hemorrhagic transformation (HT) on the one hand and enhancing neoangiogenesis and allowing the delivery of potentially therapeutic agents whose access to the central nervous system (CNS) would be otherwise impossible on the other hand
Three of the most studied chemokines in the human neuroinflammatory response are the macrophage inflammatory protein1-α (MIP1α or CCL3), the monocyte chemotactic protein-1 (MCP-1 or CCL2), and CCL5 or regulated upon activation (RANTES) [103, 113] While CCL2 and CCL3 are associated with an enlarged ischemic territory, monocyte accumulation, and microglial activation in the injured brain tissue, respectively, CCL5 has been shown to be a potent proinflammatory chemokine linked to a greater BBB disruption, possibly by enhancing matrix metalloproteases (MMP)-9 activity [103]
Summary
The blood–brain barrier (BBB) is a dynamic physiological structure that constitutes an interface between the vasculature system and the neural tissues, regulating diverse processes such as cerebral blood flow and angiogenesis, neuronal development, and synaptic activity [1]. These cells contain a higher number of mitochondria, allowing the generation of greater amounts of biological energy required to maintain BBB integrity [10] and augment its selective molecular permeability [4] BECs are polarized [8] and display numerous receptors, ion channels, and surface transport proteins along with limited vesicular transport [1, 4, 11] They possess extremely low levels of leucocyte adhesion molecules which hamper the infiltration of immune cells into the CNS and a negative surface charge that repels negatively charged compounds [1].
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