Blood–brain barrier
The blood–brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system (CNS). The blood–brain barrier is formed by brain endothelial cells, which are linked by tight junctions. The blood–brain barrier allows the passage of water, some gases, and lipid-soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are critical to neural function. Furthermore, it prevents the entry of lipophilic potential neurotoxins by way of an active transport mechanism mediated by P-glycoprotein. Astrocytes are necessary in order to create the blood–brain barrier. A few regions of the brain, including the circumventricular organs, do not have a blood–brain barrier.
The blood–brain barrier occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion of microscopic objects (e.g., bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while granting the diffusion of small or hydrophobic molecules (O2, CO2, hormones). Cells of the barrier actively transport metabolic products such as glucose across the barrier with specific proteins. This barrier also includes a thick basement membrane and astrocytic end feet.
Function: The blood–brain barrier acts very effectively to protect the brain from most pathogens. Thus, blood-borne infections of the brain are very rare. Infections of the brain that do occur are often very serious and difficult to treat. Antibodies are too big to cross the blood–brain barrier, and only certain antibiotics are able to pass. In some cases, a drug needs to be administered directly into the cerebrospinal fluid (CSF), where it can get into the brain by crossing the blood–cerebrospinal fluid barrier. However, not all drugs that are delivered directly to the CSF can effectively penetrate the CSF barrier and enter the brain. The blood–brain barrier becomes more permeable during inflammation. This allows some antibiotics and phagocytes to move across the BBB. However, this also allows bacteria and viruses to penetrate the BBB. Examples of pathogens that can traverse the BBB and the diseases they cause include toxoplasma gondii which causes toxoplasmosis, spirochetes like Borrelia which causes Lyme disease, Group B streptococci which causes meningitis in newborns, and Treponema pallidum which causes syphilis. Some of these harmful bacteria gain access by releasing cytotoxins like pneumolysin which have a direct toxic effect on brain microvascular endothelium and tight junctions.
There are also some biochemical poisons that are made up of large molecules that are too big to cross the blood–brain barrier. This was particularly important in more primitive times when people often ate contaminated food. Neurotoxins such as botulinum in food might affect peripheral nerves, but the blood–brain barrier can often prevent such toxins from reaching the central nervous system, where they could cause serious or fatal damage.
As a drug target: The blood–brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain nearly 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 puts forward 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.
Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for drug delivery/Dosage form through the BBB entail its disruption by osmotic means; biochemically by the use of vasoactive substances such as bradykinin; or even by localized exposure to high-intensity focused ultrasound (HIFU). Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters such as glucose and amino acid carriers; receptor-mediated transcytosis for insulin or transferrin; and the blocking of active efflux transporters such as p-glycoprotein. However, vectors targeting BBB transporters, such as the transferrin receptor, have turned out to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the cerebral parenchyma. Methods for drug delivery behind the BBB include intracerebral implantation (such as with needles) and convection-enhanced distribution. Mannitol can be utilized in bypassing the BBB.
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