Abstract
The blood–brain barrier (BBB) regulates the transport of molecules between the central nervous system (CNS) and blood. It consists of two components: the vascular endothelial cells forming so–called tight junctions, and the blood–cerebrospinal fluid barrier. It plays an important role in the pathogenesis and in recovery from many cerebrospinal disorders.
Paul Ehrlich was the first to observe in mice that intravenously injected acidic dyes stained the tissues of the body but not the brain. He deduced there was a barrier between systemic blood and nervous tissues. His pupil Lewandowsky visualised a capillary wall that blocked the entrance of certain molecules. And, Edwin Goldman injected trypan blue into the CSF and observed that the brain but no peripheral organs was stained — indicating the dye could not cross from CSF to the systemic bloodstream, but could leave the blood vessels of the choroid plexuses within the ventricles to enter the brain tissues.
Experiments of the heroic Russian Lina Solomonova Stern (Shtern), persecuted by Stalin, formulated the rule that every substance contained in the blood must penetrate the cerebrospinal fluid before it can exercise its effects on the nerve elements; she named the blood–brain barrier: barrière hémato–encéphalique.
This short essay was prompted by the poignant biographical article about Lina Stern [1], whose work on the blood–brain barrier (BBB) was unknown to me.
The blood–brain barrier (BBB) regulates the transport of molecules between the central nervous system (CNS) and blood. It regulates the composition, homeostatic and immune environments of the nervous system and the exchange of informational molecules. As a barrier it prevents toxic blood components, and pathogens from entering the brain. In disease, its breakdown can cause leakage of toxic blood elements into the CNS.
Clinically, BBB dysfunction [2] plays an important role in the recovery from acute forms of brain injury, strokes and seizures and in neurodegenerative disorders [3] such as multiple sclerosis and motor neuron disease.
Early experiments
Paul Ehrlich [4], whose studies on immune defense mechanisms culminated in the Nobel Prize, when looking for therapeutic agents, observed in mice that intravenously injected acidic dyes stained the tissues of the body but not the brain. He deduced there was a barrier between systemic blood and nervous tissues. However, he did not accept that permeability of cerebral vessels was different from that in other organs. Ehrlich’s pupil the neurologist Max Lewandowsky identified sodium ferrocyanide in the urine of animals within 30 minutes after intraspinal CSF injection. And he observed effects of ferrocyanide on the CNS following intrathecal injection but not after intravenous administration. He did not use the term Blut–Hirnschranke (as commonly mis–reported), but he plainly visualised a barrier when he stated: the “capillary wall must block the entrance of certain molecules [5].”
Another of Ehrlich’s students, Edwin Goldman’s experiments with the dye trypan blue confirmed this. When he injected trypan blue into the CSF the brain but no peripheral organs became heavily stained. This showed that the dye could not cross from CSF to the bloodstream, but could leave the blood vessels of the choroid plexuses within the ventricles: “Die Weg über den Liquor” [the way through the CSF] [6]. This barrier served to isolate the brain from other tissues; the extracellular fluid of the CNS is isolated from the blood.
McIntosh and Fildes in 1916 localised the BBB to the brain capillaries and recognised that CSF was not an intermediate compartment between blood and brain [7].
The blood brain barrier
The BBB consists of two components: 1. the vascular BBB, consisting of the endothelial vascular bed, and 2. the blood–cerebrospinal fluid barrier, consisting of the choroid plexus, which is a second boundary between the bloodstream and the central nervous system. It is formed by tight junction cells of the choroid plexus [8]. The anatomical site of the BBB is in brain endothelial cells (ECs) of blood vessels, which are wedged extremely closely to each other, forming so–called tight junctions. These allow only small molecules, fat–soluble molecules, and some gases to pass freely through the capillary wall and into brain tissue. Ninety–eight per cent of small molecule drugs do not cross the BBB. Some larger molecules, such as glucose, can gain entry through transporter proteins. The BBB and the blood–CSF barrier of the choroid plexus are functionally and anatomically distinct. Surrounding these vascular endothelial cells are other components of the blood–brain barrier, which communicate with the cells that form the barrier to modify its workings. This physical barrier consists of communicating junction between microvascular ECs modified by pericytes, neurons and astrocyte footplates. There is also a metabolic barrier regulating the free diffusion of soluble compounds by the expression of specific enzymes.
Barrier cells contain receptors and transporters and they can secrete substances such as cytokines, nitric oxide, and prostaglandins from either their CNS or peripheral side. Most drugs affecting the brain cross the BBB by free diffusion owing to high lipid solubility and low molecular weight [9].
Lina Solomonova Stern (Shtern) (1878–1968)
A major contributor to our understanding of the BBB is the now forgotten Lina Stern. In the 1920s, Stern published her early studies that clarified the concept of the blood–brain barrier (BBB) first indicated by Paul Ehrlich. Her experiments elaborated the physiology of this complex cerebral mechanism protecting cerebral function, later verified by Karnofsky in the 1970s using the electron microscope.
With Raymond Gautier, Stern confirmed this barrier or interface in numerous experiments and publications [10,11]. Inspired by Constantin von Monakow she formulated the rule that every substance contained in the blood must first penetrate into the cerebrospinal fluid before it can exercise its effects on the nerve elements, shown either by its physiological effects or by chemical analysis.
The blood–brain barrier (BBB) was a name she coined as barrière hémato–encéphalique [1].
We found that substances introduced into the general circulation could not all be detected in the CR. [cerebrospinal fluid] and that, on the other hand, all the substances introduced into the CR liquid were found at the end of a more or less long time in the general circulation. We have concluded that there is a kind of partitioning preventing the entry of certain substances into the CR, but allowing the release into the blood of any substance introduced into CR. At this partitioning, we have given the name of a hematoencephalic barrier.
Stern & Gautier 1922
Stern was born in 1878 in Tsarist Russia’s Latvia. Her grandfather was a rabbi. Refused medical training at Moscow University, she entered Geneva University’s medical school, graduating MD in 1903.
She embarked on original research and published extensively. Her researches included electro-stimulation of the heart, cellular metabolism, oxidation, cellular respiration, and central nervous physiology. With Frederic Battelli, Stern published 54 articles on cellular metabolism. In 1918 a new department of “Physiological Chemistry” was established at the University of Geneva where she was appointed the first woman Professor. There her work on the blood–brain barrier flourished. She published articles, on the penetration of many drugs into the brain, cerebrospinal fluid, brain homeostasis, and the blood–brain barrier in the developing brain.
But, aged forty–eight, against the counsel of her colleagues, she left this comfortable Swiss life in 1925 to become the head of physiology at the Second Moscow State University. She was widely revered and in 1929 became the director of a new institute of physiology and was elected to full membership of the Russian Academy of Sciences.
She became an advocate of suboccipital instillation of streptomycin for tuberculous meningitis, which proved effective. Two years after Hitler invaded Russia in 1941, she was awarded the Stalin Prize for her outstanding achievement in the research of the blood–brain barrier. However, as the Russians were pushing the German army back out of Russia, the paranoid Stalin decreed that Soviet Jews were infected with Zionism and part of an American threat to Russia. Her institute was disbanded and she was sacked [1]. In 1949 she was aged 71; on Stalin’s directions she was imprisoned for three years and subjected to repeated physical beating [12]. Other Jewish anti–fascists were tried in 1952 and all except Stern were executed.
After Stalin died in 1953 the military court reversed his judgments. The 76 year old Stern returned undaunted from exile and again headed the physiology laboratory at the USSR Academy of Science until her death. She remained academically active and organised international meetings.
After her ordeals, she died on March 7, 1968, an accomplished pioneering scientist and a woman of extraordinary courage. She was buried at Novodevichij cemetery in Moscow.
References
- Rosen IB. Lina Shtern and the blood brain barrier. Hektoen Int Summer 2021.
- Davson H. History of the Blood-Brain Barrier Concept 1989. In: Neuwelt E.A. (ed) Implications of the Blood Brain Barrier and Its Manipulation. Springer Boston 1989.
- Wu YC, Sonninen TM, Peltonen S, Koistinaho J, Lehtonen Š. Blood-Brain Barrier and Neurodegenerative Diseases-Modeling with iPSC-Derived Brain Cells. Int J Mol Sci. 2021; 19:22(14):7710. https://doi.org/10.3390/ijms22147710
- Ehrlich P. Sauerstoff-Bedürfniss des Organismus-Eine Farbenanalytische Studie; A. Hirschwald: Berlin, Germany, 1885.
- Lewandowski M. Zur Lehre von der Cerebrospinalflüssigkeit. Z Klin Forsch 40: 1900; 480-494.
- Goldmann E E. Vitalfarbung am Zentral-nervensystem. Abh Preuss Akad. Wissensch Physkol. Mathem. Klasse 1913; 1: 1-60.
- Mcintosh J, Fildes P. The factors which govern the penetration of arsenic (salvarsan) and aniline dyes into the brain and their bearing upon the treatment of cerebral syphilis. Brain 1916;39: 478-483. https://doi.org/10.1093/brain/39.3-4.478
- Saunders NR, Dreifuss JJ, Dziegielewska KM, Johansson PA, Habgood MD, Møllgård K, Bauer HC. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front Neurosci. 2014 Dec 16;8:404. https://doi.org/10.3389/fnins.2014.00404
- Pardridge WM. A Historical Review of Brain Drug Delivery. Pharmaceutics. 2022 Jun 16;14(6):1283.
- Stern L., Gautier R. Recherches sur le liquide céphalo-rachidien. Arch. Internationales de Physiologie. 1921; 17: 138-192. https://doi.org/10.3109/13813452109146211
- Stern L., Gautier R. Recherches sur le liquide céphalo-rachidien. Les rapports entre le liquide céphalo-rachidien et les éléments nerveux de l’axe cérébrospinal. Arch. Int. Physiol. 1922; 17: 391-448. https://doi.org/10.3109/1381345220914621
- Sarikcioglu L. Lina Stern (1878-1968): an outstanding scientist of her time. Childs Nerv Syst 2017;33: 1027-1029. https://doi.org/10.1007/s00381-017-3392-3
