The surface area developed by the endothelium of the penetrating cerebral arteries and veins is also modest by comparison to the surface developed by the microvessel network. (2) Circumventricular organs, however, do not constitute a significant route of entry into the whole CNS for blood-borne pharmacological compounds. The presence of permeable capillaries in these latter structures is relevant to their functions which include sensing of blood-borne hormones and other products, and central control of diverse homeostatic processes. By contrast, the capillaries of circumventricular organs such as the area postrema or the median eminence are highly permeable and form the exception among brain structures. (1) All capillaries of gray and white matter structures including those of the hypothalamus display a tight barrier phenotype. This barrier develops a large surface area of exchange between the blood and the neuropil, with an average of 100 cm 2 per gram of brain tissue in adult mammal. The barrier between the blood and the brain or spinal cord parenchyma proper, hereafter referred to as the blood–brain barrier (BBB), is formed by the endothelium of the cerebral microvessel (Figures 1 and 2A). They are collectively named blood–brain interfaces and are present in various locations as illustrated in Figure 1. By restricting both paracellular and transcellular diffusion of hydrophilic and lipophilic substances, these cellular interfaces provide the strictly controlled environment required for CNS development and functions. All these mechanisms could be explored and manipulated to improve macromolecule delivery to the brain.ĭelivery of pharmacologically active molecules, especially macromolecules, to the brain is challenged by specific properties of the cells forming the interfaces between the blood and the central nervous system (CNS). An additional mechanism specific to the BCSFB mediates the transport of selected plasma proteins from blood into CSF in the developing brain. They enable brain penetration of selected polypeptides and proteins, or inversely macromolecule efflux as it is the case for immnoglobulins G. Receptor-mediated endocytotic and transcytotic mechanisms are active in the barriers. These various molecular effectors differently distribute between the two barriers. Other bioactive metabolites, lipophilic toxic xenobiotics or pharmacological agents are restrained from accumulating in the brain by several ATP-binding cassette efflux transporters, multispecific solute carriers, and detoxifying enzymes. Small organic compounds such as nutrients, micronutrients and hormones are transported into the brain by specific solute carriers.
Inorganic ion transport is highly regulated across the barriers. Vesicular traffic is limited in the cerebral endothelium and abundant in the choroidal epithelium, yet without evidence of active fluid phase transcytosis. Tight junctions at each barrier comprise a distinctive set of claudins from the pore-forming and tightening categories that determine their respective paracellular barrier characteristics. It is specified by various signaling molecules from the embryonic dorsal midline, such as bone morphogenic proteins, and grows under the influence of Sonic hedgehog protein. The tight choroid plexus epithelium develops very early during embryogenesis. Later in development, astrocytes also play a role in blood–brain barrier maintenance. Cerebral microvessels acquire a barrier phenotype early during cerebral vasculogenesis under the influence of the Wnt/β-catenin pathway, and of recruited pericytes.
Although both barriers develop extensive surface areas of exchange between the blood and the neuropil or the CSF, the molecular fluxes across these interfaces are tightly regulated. Blood–brain interfaces comprise both the blood–brain barrier located at the endothelium of the brain microvessels and the blood–CSF barrier located at the epithelium of the choroid plexuses. As a correlate, the delivery of pharmacologically active molecules and especially macromolecules to the brain is challenged by the barrier properties of these interfaces. The brain develops and functions within a strictly controlled environment resulting from the coordinated action of different cellular interfaces located between the blood and the extracellular fluids of the brain, which include the interstitial fluid and the cerebrospinal fluid (CSF).
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