The blood-brain barrier (BBB) plays a vital role in regulating the trafficking of fluid, solutes and cells at the blood-brain interface and maintaining the homeostatic microenvironment of the CNS. Under pathological conditions, such as ischemic stroke, the BBB can be disrupted, followed by the extravasation of blood components into the brain and compromise of normal neuronal function. This article reviews recent advances in our knowledge of the mechanisms underlying BBB dysfunction and recovery after ischemic stroke. CNS cells in the neurovascular unit, as well as blood-borne peripheral cells constantly modulate the BBB and influence its breakdown and repair after ischemic stroke. The involvement of stroke risk factors and comorbid conditions further complicate the pathogenesis of neurovascular injury by predisposing the BBB to anatomical and functional changes that can exacerbate BBB dysfunction. Emphasis is also given to the process of long-term structural and functional restoration of the BBB after ischemic injury. With the development of novel research tools, future research on the BBB is likely to reveal promising potential therapeutic targets for protecting the BBB and improving patient outcome after ischemic stroke.

Experimental autoimmune encephalomyelitis (EAE) is an infl ammatory demyelinating disease of the central nervous system (CNS) induced in laboratory animals by active immunization with myelin antigens or by the adoptive transfer of myelin-specifi c CD4 + T cells. It is widely used as an animal model of multiple sclerosis (MS) and as a prototype of organ-specifi c autoimmunity. Until recently, EAE and MS were considered Th1 diseases, mediated by IL-12p70 -polarized, IFN-␥ -producing eff ector cells. This impression was based, in large part, on the association between clinical disease activity and expression of IFN-␥ and IL-12p40 (a subunit of IL-12p70) in CNS tissues, cerebrospinal fl uid, and circulating leukocytes ( 1 -3 ). In addition, activated macrophages are the predominant leukocyte in CNS infi ltrates of affl icted animals and patients, similar to the infi ltrates that characterize Th1-dependent hypersensitivity and antimicrobial responses in the periphery ( 4, 5 ).Recent fi ndings, however, suggest that the cytokine pathways underlying encephalitogenic T cell development and function are more complex than previously appreciated. Defi ciency of IL-17 or IL-23 (a heterodimeric monokine composed of IL-12p40 and p19 chains that expands and/or stabilizes Th17 cells) ( 6, 7 ) confers partial or complete resistance, respectively, against MOG 35-55 -induced EAE in C57BL/6 mice, whereas defi ciency of IFN-␥ or IL-12p70 does not ( 8 -10 ). Furthermore, myelin-specifi c

The blood-brain barrier (BBB) is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules into brain, and preserves ionic homeostasis within the brain microenvironment. BBB properties are primarily determined by junctional complexes between the cerebral endothelial cells. These complexes are comprised of tight and adherens junctions. Such restrictive angioarchitecture at the BBB reduces paracellular diffusion, while minimal vesicle transport activity in brain endothelial cells limits transcellular transport. Under normal conditions, this largely prevents the extravasation of large and small solutes (unless specific transporters are present) and prevents migration of any type of blood-borne cell. However, this is changed in many pathological conditions. There, BBB disruption (“opening”) can lead to increased paracellular permeability, allowing entry of leukocytes into brain tissue, but also contributing to edema formation. In parallel, there are changes in the endothelial pinocytotic vesicular system resulting in the uptake and transfer of fluid and macromolecules into brain parenchyma. This review highlights the route and possible factors involved in BBB disruption in a variety of neuropathological disorders (e.g. CNS inflammation, Alzheimer’s disease, Parkinson’s disease, epilepsy). It also summarizes proposed signal transduction pathways that may be involved in BBB “opening”.

The expression of the monocyte chemoattractant protein-1 (MCP-1) receptor CCR2 by brain endothelial cells suggests that MCP-1 may have other functions than purely driving leukocyte migration into brain parenchyma during inflammation. This study examines one of these potential novel roles of MCP-1 regulation of endothelial permeability using primary cultures of mouse brain endothelial cells. MCP-1 induces reorganization of actin cytoskeleton (stress fiber formation) and redistribution of tight junction proteins, ZO-1, ZO-2 occludin and claudin-5, from the Triton X-100-soluble to the Triton X-100-insoluble fractions. These morphological changes are associated with a decrease in transendothelial electrical membrane resistance and an increase in [14C]inulin permeability. MCP-1 did not induce these events in brain endothelial cells prepared from mice genotype CCR2–/–. The Rho kinase inhibitor Y27632 and inhibition of Rho (C3 exoenzyme, and dominant negative mutant of Rho, RhoT19N) prevented MCP-1-induced stress fiber assembly, reorganization of tight junction proteins and alterations in endothelial permeability. In all, this suggests that a small GTPase Rho and Rho kinase have a pivotal role in MCP-1-induced junction disarrangement. These data are the first to strongly suggest that MCP-1, via CCR2 present on brain endothelial cells, contributes to increased brain endothelial permeability.

The present study was designed to elucidate the effects of the chemokine monocyte chemoattractant protein (MCP-1) on blood-brain barrier (BBB) permeability. Experiments were conducted under in vitro conditions (coculture of brain endothelial cells and astrocytes) to study the cellular effects of MCP-1 and under in vivo conditions (intracerebral and intracerebroventricular administration of MCP-1) to study the potential contribution of MCP-1 to BBB disruption in vivo. Our results showed that MCP-1 induces a significant increase in the BBB permeability surface area product for fluorescein isothiocyanate (FITC)-albumin under in vivo conditions, particularly during prolonged (3 or 7 days) exposure (0.09670.008 versus 0.03170.005 lL/g min in controls at 3 days, Po0.001). Monocyte chemoattractant protein-1 also enhanced (17-fold compared with control) the permeability of the in vitro BBB (coculture) model. At the cellular level, MCP-1 causes alteration of tight junction (TJ) proteins in endothelial cells (redistribution of TJ proteins determined by Western blotting and loss of immunostaining for occludin, claudin-5, ZO-1, ZO-2). Monocyte chemoattractant protein-1-induced alterations in BBB permeability are mostly realized through the CCR2 receptor. Absence of CCR2 diminishes any effect of MCP-1 on BBB permeability in vitro and in vivo. The permeability surface area product for FITC-albumin after 3 days exposure to MCP-1 was 0.09670.006 and 0.0327 0.007 lL/g min, in CCR2 þ / þ and CCR2À/À mice, respectively (Po0.001). Monocytes/macrophages also participate in MCP-1-induced alterations in BBB permeability in vivo. Monocytes/macrophages depletion (by clodronate liposomes) reduced the effect of MCP-1 on BBB permeability in vivo B2 fold. Our results suggest that, besides its main function of recruiting leukocytes at sites of inflammation, MCP-1 also plays a role in 'opening' the BBB.