Blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system, thus protecting the brain from harmful or unwanted substances in the blood.[1] The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane.[2] This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.[3]
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, while allowing the diffusion of hydrophobic molecules (O2, CO2, hormones) and small non-polar molecules.[4][5] Cells of the barrier actively transport metabolic products such as glucose across the barrier using specific transport proteins.[6] The barrier also restricts the passage of peripheral immune factors, like signaling molecules, antibodies, and immune cells, into the CNS, thus insulating the brain from damage due to peripheral immune events.[7]
Specialized brain structures participating in sensory and secretory integration within brain neural circuits—the circumventricular organs and choroid plexus—have in contrast highly permeable capillaries.[8]
Therapeutic research[edit]
As a drug target[edit]
The blood–brain barrier 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.[1] Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders.[27][28] 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 to be clinically effective.[27] The BBB represents an obstacle to some drugs reaching the brain, thus to overcome this barrier some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system.[29]
Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for drug delivery to the brain in unit doses through the BBB entail its disruption by osmotic means, or biochemically by the use of vasoactive substances, such as bradykinin,[30] or even by localized exposure to high-intensity focused ultrasound (HIFU).[31]
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.[27] Some studies have shown that vectors targeting BBB transporters, such as the transferrin receptor, have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area.[27][32]
Prediction[edit]
There have been many attempts to correlate the experimental blood–brain barrier permeability with physicochemical properties. In 1988, the first QSAR study of brain–blood distribution conducted reported the in vivo values in rats for a large number of H2 receptor histamine agonists.[40]
The first papers modelling blood-brain barrier permeability identified three properties, i.e., molecular volume, lipophilicity, and hydrogen bonding potential, as contributing to solute transport through the blood-brain barrier.[41] A 2022 dataset selected different classification models[42] based on molecular fingerprints,[43] MACCS166 keys[44] and molecular descriptors.[45]
History[edit]
A 1898 study observed that low-concentration "bile salts" failed to affect behavior when injected into the blood of animals. Thus, in theory, the salts failed to enter the brain.[46]
Two years later, Max Lewandowsky may have been the first to coin the term "blood–brain barrier" in 1900, referring to the hypothesized semipermeable membrane.[47] There is some debate over the creation of the term blood–brain barrier as it is often attributed to Lewandowsky, but it does not appear in his papers. The creator of the term may have been Lina Stern.[48] Stern was a Russian scientist who published her work in Russian and French. Due to the language barrier between her publications and English-speaking scientists, this could have made her work a lesser-known origin of the term.
All the while, bacteriologist Paul Ehrlich was studying staining, a procedure that is used in many microscopy studies to make fine biological structures visible using chemical dyes.[49] As Ehrlich injected some of these dyes (notably the aniline dyes that were then widely used), the dye stained all of the organs of some kinds of animals except for their brains.[49] At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye.[47]
However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich's students) injected the dye directly into the cerebrospinal fluid of animal brains. He found then the brains did become dyed, but the rest of the body did not, demonstrating the existence of a compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found.