The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

Abstract

Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue) exclusion from the brain when injected systemically, but not when injected directly into it. Rarely cited are earlier experiments of Bouffard and of Franke who showed methylene blue and trypan red stained all tissues except the brain. The term “blood-brain barrier” “Blut-Hirnschranke” is often attributed to Lewandowsky, but it does not appear in his papers. The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern and colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling. As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all the evidence and assessing its quality, rather than selecting papers that supports a preconceived notion or intuitive belief. This review attempts to right the wrongs. Based on careful translation of original papers, some published a century ago, as well as providing discussion of studies claiming to show barrier immaturity, we hope that readers will have evidence on which to base their own conclusions.

Disorders of Acid-Base Balance: New Perspectives

“…In addition, due to different permeabilities of the blood brain barrier for carbon dioxide, hydrogen ion, and bicarbonate, movement of these species into the CNS, each with a different time course, results in nonsteady state transitional changes in pH of the CNS. These transitions are at times paradoxical to the pH of the peripheral blood [6] .…”

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

“…Taken together, it is likely that dysfunction of BBB is caused by multiple prenatal and postnatal risk factors. Because BBB function is immature at early developmental stages (Saunders et al, 2014), cerebral neural cells in fetuses, infants, and young children are presumably vulnerable to these factors. Therefore, it is possible that BBB disturbances are related to ASD.…”

Circumventing the blood–brain barrier

“…But Ehrlich's student Edwin Goldmann later managed to stain the brain by injecting dye directly into the cerebrospinal fluid. Together, the findings suggested the brain was somehow protected from general circulation (1,2).…”

“…Direct evidence for such a barrier, however, would await the rise of the electron microscope in the 1950s and 60s, which ultimately revealed that strands of proteins joined together the endothelial cells lining the brain's vasculature, walling off passing molecules. These so-called "tight junctions" are also found elsewhere in the circulatory system, but they are especially tight in the brain, restricting flow down to 10-15 angstroms (1,2).…”