The Blood Brain Barrier

The BBB maintains the flux of ions, water-soluble nutrients, and metabolites to titrate the specific composition of extracellular fluid in the central nervous system. The brain parenchyma is contained within an immunologically separate compartment under tight volumetric control. This compartmentali-zation is achieved and maintained by a combination of specific morphologic features and biochemical factors.

The BBB consists of endothelial cells bridged by tight junctions and adjoined by foot processes of astroglia. Endothelial cells form the inner lining of all vessels and have common properties that include a nonthrombogenic luminal surface, a basement membrane, and the production of active substances. Astrocytic foot processes extend to form a tight network that enmeshes the outer surface of brain capillaries. The endothelial architecture of the cerebral circulation is distinct from other vascular territories. Early in life, the cerebrovascular endothelium becomes almost completely impermeable, thereby isolating the brain from the systemic circulation. The BBB exists throughout the central nervous system, leaving only specific areas, such as the choroid plexus and the circumventricular organs, devoid of this structure. The choroid plexus is responsible for the production of CSF, modifying plasma from the cerebral circulation to maintain the protective fluid compartment of the ventricular system. The CSF circulates from the ventricular system into the subarachnoid space where it functions as a cushion for the brain, protecting it from trauma. The circumventricular organs include chemosensitive and neurosecretory sites that are involved in body fluid turnover, regulation of fluid osmolarity and extracellular sodium content, and cardiovascular function.

Several structural features of the BBB account for the specialized function of this cellular layer. Complex interendothelial junctions prevent even small ions from entering the brain parenchyma. Only lipid-soluble substances are allowed to diffuse through this layer. Pinocytosis, the transport of materials within small intracellular vesicles, is necessary for most substances to traverse the endothelial layer. Electron microscopy of the BBB demonstrates the close opposition of endothelial cells, including a paucity of vesicular transport and a high density of mitochondria. The mitochondrial content of brain endothelia is approximately 10 or 11%, compared to 2.7% in other blood vessels. This elevated concentration of mitochondria is necessary for the high rate of metabolic activity that occurs. The passage of polar molecules, including many amino acids, is accomplished by several specialized transport systems.

The functional properties of the BBB include a high transendothelial potential and resistance, with a high reflection coefficient and low hydraulic conductivity. The intracellular compartment of the endothelial layer has marked enzyme activity associated with multiple transport systems. Water transport across the BBB is under close neurogenic and endocrine control. Biologically active agents that alter the BBB include substance P, adenosine nucleotides, endothelin-1, calcium entry blockers, metalloproteinases, cytokines, vascular endothelial growth factor or vascular permeability factor (VEGF/VPF), and antibodies to filamentous hemagglutanin. Several cytokines, including interleukins, tumor necrosis factor-a (TNF-a), and platelet-activating factor (PAF), are active at the BBB. Vasoactive substances can increase BBB permeability by activating cyclic nucleotide-generating enzymes or by increasing the rate of lipolysis through phospholi-pases. Vasodilators such as arachidonic acid, nora-drenaline, and histamine may also increase cytoplasmic ionized calcium and activate microvascu-lar guanylate cyclase. These actions result in increased pinocytosis and macromolecular transport. Modulation of BBB permeability has been the focus of recent therapeutic interventions for brain tumors, employing steroidal substances and chemotherapeutic agents.

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Anxiety and Depression 101

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