*2.2. Blood Brain Barrier in Ischemic Stroke*

Blood brain barrier (BBB) plays an important role in ischemia/reperfusion (I/R). During ischemic stroke, there are two phases of BBB breaking. In the early phase of reperfusion (6 h), endothelial transcytosis dominates in increased permeability of BBB, and it may be associated with endothelial vesicle transport [27]. In the later phase, BBB is disrupted because of the loss of integrity of endothelial tight junctions (TJs). Studies showed that the structural changes of TJs occurred at 48–58 h after middle cerebral artery occlusion (MCAO) in mice [28], and these changes were associated with the degradation of TJs by matrix metalloproteinases (MMPs) [29]. MMPs also degraded extracellular matrix proteins of basal membrane of BBB, such as type IV collagen [30].

The immune response also causes the loss of BBB integrity, leading to cell death in stroke [31]. Microglia are macrophages existing in the brain, and they become activated in response to ischemic stroke, which cause the production of ROS, cytokines (e.g., TNF-α, IL-1β, and IL-6) and chemokines (e.g., macrophage inflammatory proteins-1alpha (MIP-1α)/CCL3, monocyte chemoattractant protein-1 (MCP-1)/CCL-2 and chemokine (C-X-C motif) ligand-1 (CXCL-1)). These inflammatory products act on endothelial cells to activate the NF-κB pathway for expression of adhesion molecules, such as vascular cell adhesion protein (VCAM), ICAM-1, and P-selectin. These molecules support leukocyte recruitment to invade brain parenchymal tissues [32], thus increasing the brain permeability [33].

Blood brain barrier maintains the brain homeostasis, but ischemic stroke disrupts this barrier, resulting in increased vascular permeability. As we discussed, the permeability is regulated by transcellular pathways in the early stage and the breaking TJs in the later stage [28]. Therapeutics delivery systems to ischemic stroke lesions can be designed based on its pathogenesis.
