question: How does the blood brain barrier work? Specifically what happens at the crossover?
comment: In normal blood vessels, the wall of the vessel is made of cells, but it contains periodic holes that allow larger molecules like proteins and even entire cells to move through into the extracellular fluid. The BBB has much tighter seals between cells and doesn't possess these holes, so the only molecules that can move through are those small and polar-enough to do so by passive diffusion (moving straight through the cell membrane) and those that the BBB cells specifically want to move through - they have proteins called channels in their membranes that can pick up key molecules like glucose and pull them in.
passages: Section::::Clinical significance.
  
  Section::::Clinical significance.:As a drug target.
   Section::::Physiology.
  
  The main function of the blood–brain barrier is to protect the brain and keep it isolated from harmful toxins that are potentially in the blood stream. It accomplishes this because of its structure, as is usual in the body that structure defines its function. The tight junctions between the endothelial cells prevent large molecules as well as many ions from passing between the junction spaces. This forces molecules to go through the endothelial cells in order to enter the brain tissue, meaning that they must pass through the cell membranes of the endothelial cells.
   Technically, the BBB is a shorthand for the Blood-CNS barrier, which has two parts: the Blood-Brain portion and the Blood-Spinal Cord Barrier portion. The two parts are often breached simulatenously, but may be independently breached.
  
  Section::::Structure.
   During systemic inflammation, whether in the form of infection or sterile inflammation, the BBB may become leaky to blood-borne compounds. Such changes may be part of a productive host response to systemic inflammation, or may lead to deleterious consequences within the central nervous system. These changes may also affect the course of multiple sclerosis or Alzheimer's disease.
  
  Section::::History.
   Casomorphin is a heptapeptide and could be able to pass the BBB.
  
  Section::::Disease.
  
  Section::::Disease.:Meningitis.
   Section::::Disease.:Brain abscess.
   Several areas of the human brain are not on the brain side of the BBB. Some examples of this include the circumventricular organs, the roof of the third and fourth ventricles, capillaries in the pineal gland on the roof of the diencephalon and the pineal gland. The pineal gland secretes the hormone melatonin "directly into the systemic circulation", thus melatonin is not affected by the blood–brain barrier.
  
  Section::::Structure.:Development.
   Similar to the blood–brain barrier, the blood–CSF barrier functions to prevent the passage of most blood-borne substances into the brain, while selectively permitting the passage specific substances into the brain and facilitating the removal of brain metabolites and metabolic waste into the blood. Despite the similar function between the BBB and BCSFB, each facilitates the transport of different substances into the brain due to the distinct structural characteristics between the two barrier systems. For a number of substances, the BCSFB is the primary site of entry into brain tissue.
   Section::::Clinical significance.:As a drug target.:Nanoparticles.
  
  Nanotechnology may also help in the transfer of drugs across the BBB. Recently, researchers have been trying to build liposomes loaded with nanoparticles to gain access through the BBB. More research is needed to determine which strategies will be most effective and how they can be improved for patients with brain tumors. The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored.
   Section::::Function.
  
  The blood–brain barrier acts effectively to protect the brain from circulating pathogens. Accordingly, blood-borne infections of the brain are rare. Infections of the brain that do occur are often difficult to treat. Antibodies are too large to cross the blood–brain barrier, and only certain antibiotics are able to pass. In some cases, a drug has to be administered directly into the cerebrospinal fluid (CSF) where it can enter the brain by crossing the blood–cerebrospinal fluid barrier.
   The blood–brain barrier results from the selectivity of the tight junctions between endothelial cells in CNS vessels, which restricts the passage of solutes. At the interface between blood and the brain, endothelial cells are stitched together by these tight junctions, which are composed of smaller subunits, frequently biochemical dimers, that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), or ESAM, for example. Each of these transmembrane proteins is anchored into the endothelial cells by another protein complex that includes ZO-1 and associated proteins.
   The blood–brain barrier is formed by special tight junctions between the epithelial cells that surround the brain tissue. All tissue is separated by this layer of epithelial cells, however only the brain epithelial cells have these tight junctions that do not allow larger molecules to pass between them. The structure of these tight junctions was first determined in the 1960s by Tom Reese, Morris Kranovsky and Milton Brightman. These tight junctions are formed through the tight apposition of the endothelial cells with one another. Furthermore, astrocytic, "end feet" "the terminal regions of the astrocytic processes surround the outside of the capillary endothelial cell". The astrocytes are glial cells that are restricted to the brain and spinal cord that work to maintain an appropriate environment for neural signaling. The connection between these glial and endothelial cells is not very well known but it "may reflect an influence of the astrocytes on the formation and the maintenance of the blood–brain barrier.
   Specialized structures participating in sensory and secretory integration within neural circuits – the circumventricular organs and choroid plexus – do not have a blood–brain barrier.
  
  The blood–brain barrier restricts the passage of pathogens, the diffusion of solutes in the blood, and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of hydrophobic molecules (O, CO, hormones) and small polar molecules. Cells of the barrier actively transport metabolic products such as glucose across the barrier using specific transport proteins.
  
  Section::::Terms.
   Section::::Disease.:Epilepsy.
  
  Epilepsy is a common neurological disease that is characterized by recurrent and sometimes untreatable seizures. Several clinical and experimental data have implicated the failure of blood–brain barrier function in triggering chronic or acute seizures. Some studies implicate the interactions between a common blood protein (albumin) and astrocytes. These findings suggest that acute seizures are a predictable consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition, expression of drug resistance molecules and transporters at the BBB are a significant mechanism of resistance to commonly used anti-epileptic drugs.
  
  Section::::Disease.:Multiple sclerosis.
   Permeable capillaries of the sensory CVOs (area postrema, subfornical organ, vascular organ of the lamina terminalis) enable rapid detection of circulating signals in systemic blood, while those of the secretory CVOs (median eminence, pineal gland, pituitary lobes) facilitate transport of brain-derived signals into the circulating blood. Consequently, the CVO permeable capillaries are the point of bidirectional blood–brain communication for neuroendocrine function.
  
  Section::::Function.:Specialized permeable zones.
   Delivering drugs across the blood–brain barrier is one of the most promising applications of nanotechnology in clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a predefined sequence, which is very important in the delivery of drugs across the blood–brain barrier.
   The blood–brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. In its neuroprotective role, the blood–brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts.
   Originally, experiments in the 1920s seemed to (wrongly) show that the blood–brain barrier (BBB) was still immature in newborns. This was due to an error in methodology (the osmotic pressure was too high and the delicate embryonal capillary vessels were partially damaged). It was later shown in experiments with a reduced volume of the injected liquids that the markers under investigation could not pass the BBB. It was reported that those natural substances such as albumin, α-1-fetoprotein or transferrin with elevated plasma concentration in the newborn could not be detected outside of cells in the brain. The transporter P-glycoprotein exists already in the embryonal endothelium.
   The blood–brain barrier is composed of high-density cells restricting passage of substances from the bloodstream much more than do the endothelial cells in capillaries elsewhere in the body. Astrocyte cell projections called astrocytic feet (also known as "glia limitans") surround the endothelial cells of the BBB, providing biochemical support to those cells. The BBB is distinct from the quite similar blood–cerebrospinal fluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the blood–retinal barrier, which can be considered a part of the whole realm of such barriers.
   Lewandowsky coined the term ""Blood–brain barrier"" in 1900, referring to the hypothesized semipermeable membrane which separated the human central nervous system from the rest of the body's vasculature, and which prevented the entry of certain compounds from entering the brain when injected into the bloodstream. Two years earlier, researchers Arthur Biedl and R. Kraus had formed a similar hypothesis when low-concentration "bile salts" failed to affect behavior (and thus, in theory, had failed to enter the brain) when injected into the bloodstream of animals.
   Section::::Design.
   Section::::Possible solutions.
  
  Section::::Possible solutions.:Exosomes to deliver treatments across the blood–brain barrier.
   The border zones between brain tissue "behind" the blood–brain barrier and zones "open" to blood signals in certain CVOs contain specialized hybrid capillaries that are leakier than typical brain capillaries, but not as permeable as CVO capillaries. Such zones exist at the border of the area postrema–nucleus tractus solitarii (NTS), and median eminence–hypothalamic arcuate nucleus. These zones appear to function as rapid transit regions for brain structures involved in diverse neural circuits – like the NTS and arcuate nucleus – . The permeable capillary zone shared between the median eminence and hypothalamic arcuate nucleus is augmented by wide pericapillary spaces, facilitating bidirectional flow of solutes between the two structures, and indicating that the median eminence is not only a secretory organ, but may also be a sensory CVO.
   Section::::Drug delivery to the blood–brain barrier.
   Neuromyelitis optica, also known as Devic's disease, is similar to and is often confused with multiple sclerosis. Among other differences from MS, a different target of the autoimmune response has been identified. Patients with neuromyelitis optica have high levels of antibodies against a protein called aquaporin 4 (a component of the astrocytic foot processes in the blood–brain barrier).
  
  Section::::Disease.:De Vivo disease.
  