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Hemato-encephalic barrier

The relationship between brain tissue cells and the capillary:
1. Ependyma
2. Neuron
3. Axon
4. Oligodendrocyte
5. Astrocyte
6. Myelin
7. Microglia
8. Capillary
3D-model of the hemato-encephalic barrier

Hemato-encephalic barrier (BBB) [1] (from the ancient Greek. Αἷμα , genus. N. Ααματος - “blood” and other Greek: έγκέφαλο - “brain”) - the physiological barrier between the circulatory system and the central nervous system by the system . All vertebrates have a BBB.

The main function of the BBB is to maintain brain homeostasis . It protects nervous tissue from microorganisms circulating in the blood , toxins , cellular and humoral factors of the immune system that perceive brain tissue as foreign. The BBB performs the function of a highly selective filter through which nutrients, bioactive substances enter the brain from the arterial bed; in the direction of the venous bed with the glymphatic flow, waste products of the nervous tissue are removed.

However, the presence of BBB complicates the treatment of many diseases of the central nervous system , as it does not miss a number of drugs .

Development of the hemato-encephalic barrier concept

The founder of the teaching on the GEB Paul Ehrlich
Max Levandovsky (1876–1916) first used the term “Blut-Hirn-Schranke” (the partition between blood and brain ) in 1900

The first evidence of the existence of the BBB was obtained in 1885 by Paul Ehrlich . He discovered that the dye injected into the bloodstream of the rat had spread to all organs and tissues except the brain [2] . In 1904, he made the wrong assumption that the dye does not penetrate into the brain tissue when administered intravenously, since it has no affinity for it [3] . The South African surgeon Edwin Goldman (1862–1913), a student of Erlich, discovered in 1909 that the intravenous trypan blue dye does not penetrate into the brain tissue, but stains the choroid plexus of his ventricles [4] . In 1913, he showed that the dye injected into the spinal fluid of a dog or horse penetrates into the tissue of the brain and spinal cord, while peripheral organs and tissues do not stain [5] . Based on these experiments, Goldman suggested the existence of a barrier between the brain and blood that delays neurotoxic substances [6] .

In 1898, Viennese pathologists Arthur Bidl (1869–1933) and Rudolf Kraus (1868–1932) showed that with the introduction of bile acids into the bloodstream, a neurotoxic effect did not occur, but coma was developed when injected directly into the brain tissue [7] . German neuropathologist Max Lewandowski repeated the experiments of Beadle and Kraus with potassium hexacyanoferrate . Having obtained similar results, he first used the term “Blut-Hirn-Schranke” (the partition between blood and brain , 1900), which was subsequently also adopted in the English-language literature ( blood-brain barrier ) [8] [9] .

In 1915, the Swiss neuroanatom Konstantin von Monakov in Zurich suggested that the choroid plexus and neuroglia perform a barrier function. [10] In subsequent years, he and his collaborators published several entirely histological works on the choroid plexus, which one of his students ( Chilean psychoanalyst Fernando Allende-Navarro, 1890–1981), in a 1925 publication , calls the “Ecto-mesodermal barrier” ( Fr. Barrière ecto-mésodermique ).

 
The term "hemato-encephalic barrier" in 1921 was proposed by Lina Stern , the first woman professor (professor extraordinaire) of the University of Geneva (1918) [11]

The term "hemato-encephalic barrier" ( fr. Barrière hémato-encéphalique ) was introduced into scientific use [10] by the Swiss , and then by the Soviet physiologist Lina Solomonovna Stern (first woman - member of the Academy of Sciences of the USSR ) [12] in collaboration with his students Ernest Rotlin and Raymond Gautier communication to the Geneva Medical Society (Société de Biologie et Médecine) for April 21, 1921 [13] [14] :

Between the blood, on the one hand, and the cerebrospinal fluid, on the other, there is a special apparatus or mechanism capable of sifting substances that are commonly present in the blood or that have accidentally entered it. We propose to call this hypothetical mechanism, which allows some substances to pass through and slows down or stops the penetration of other substances, as a hemato-encephalic barrier. [15] [16]

The first messages of Lina Stern and Ernest Rothlin at a meeting of Société de physique et d'histoire naturelle de Genève and their publication in the Schweizer Archive of Neurologie und Psychiatrie about the presence of a protective barrier between the brain and the bloodstream relate to 1918 . [17] Stern and Rotlin, by means of the thinnest cannula, managed to inject 1 mg of curare into the space of the fourth ventricle of an experimental animal and record the slow diffusion of neurotoxin from the cerebrospinal fluid through the leptomeningial membranes into the deep nuclei of the cerebellum . In 1921, L. S. Stern published the first review article in the Schweizer Archive für Neurologie und Psychiatrie, and in 1923 her influential work La Barriere Hémato-Encéphalique dans les conditions normales et pathologiques, included in a two-volume collective collection devoted to 70 anniversary of Konstantin von Monakov (1853-1930) and published by the same magazine. [18] In the last review, in addition to summarizing the experimental and histological studies of the BBB, its role in normal physiology and neuropathology, Stern also considers its role in the pharmacodynamics and pharmacokinetics of neurotropic drugs. In subsequent years, Stern, based on an analysis of extensive experimental material, formulated the provisions of the BBB and determined its importance for the activity of the central nervous system [19] . In 1935, under her editorship, the first collective collection was published, entirely devoted to this topic (“Hemato-encephalic barrier”, M. — L.: Biomedgiz, 1935). For her research on the blood-brain barrier, L. S. Shtern in 1943 was awarded the Stalin Prize , the monetary component of which she donated for the construction of an ambulance plane. [20]

In the 1930s, a distinction was made between the hemato-encephalic and hematopoietic barrier [6] [21] [22] .

The morphological structures responsible for the BBB were studied in detail in the 1960s by electron microscopy [23] [24] .

Functions

The mass of the human brain is approximately 2% of the mass of its body. At the same time, oxygen consumption by the central nervous system makes up 20% of the total oxygen consumption by the body. Also, in contrast to other organs, the brain has the lowest nutrient supply. Nerve cells cannot provide their energy needs through anaerobic glycolysis alone. The cessation of blood flow to the brain within a few seconds leads to loss of consciousness, and after 10 minutes neuron death occurs [23] . Such energy needs of the brain are provided by active transport of oxygen and nutrients through the BBB [25] .

The normal functioning of the brain is also possible only in terms of electrolyte and biochemical homeostasis . Fluctuations in pH , potassium concentration in the blood and other indicators should not affect the state of the nervous tissue. Neurotransmitters circulating in the bloodstream should not penetrate into the nervous tissue, where they could alter the activity of neurons [23] . Also, the brain must be protected from foreign agents, such as xenobiotics and pathogens, from entering it. BBB is also an immunological barrier, as it is impermeable to many microorganisms, antibodies and leukocytes [26] [27] .

The system of blood vessels of the central nervous system has a number of structural and functional features that distinguish them from the vessels of other organs and tissues. These features provide functions of nutrition, excretion of waste products and maintain homeostasis [23] .

Violations of the BBB can cause damage to the central nervous system. A number of neurological diseases are directly or indirectly associated with damage to the BBB [25] .

Build

 
Comparative scheme of the structure of the peripheral and cerebral capillaries
 
BBB structure - from brain tissue to tight contact
 
Schematic structure of the vascular wall of the artery, arterioles and capillary of the brain

The main element of the BBB structure are endothelial cells . A feature of cerebral vessels is the presence of tight contacts between endothelial cells. The structure of the BBB also includes pericytes and astrocytes [23] . The intercellular spaces between endothelial cells, pericytes, and astrocytes of the BBB neuroglia are smaller than the interstices between cells in other tissues of the body. These three types of cells are the structural basis of the BBB not only in humans, but also in most vertebrates [28] [29] .

Endothelium

Capillary vessels are lined with endothelial cells. The vascular endothelium of most tissues contains open spaces (fenestration) with a diameter of about 50 nm and intercellular gaps from 100 to 1000 nm. Through these gaps, water and substances dissolved in it circulate between the blood and the extracellular space. A distinctive feature of the vessels of the central nervous system is the absence of both fenestrations and intercellular cracks between endothelial cells [30] . Thus, the endothelial lining of the capillaries of the brain is continuous [31] .

Another difference between the endothelium of cerebral capillaries and the peripheral is the low content of pinocytotic vesicles (vesicles) in them [9] [32] .

The number of mitochondria in the endothelial cells of the blood vessels of the brain is 5-10 times higher than in the endothelium of peripheral vessels. Such a high content of mitochondria is associated with significant energy needs of the BBB endothelial cells that carry out active transport and metabolism [27] . (Mitochondria are organelles in which the synthesis of ATP molecules , which are the main source of energy for cells, occurs.)

The BBB is also a metabolic or enzymatic (enzymatic) barrier [6] [33] [34] [35] [36] . A number of enzymes are located on the surface of the cell membranes of the endothelial cells of the BBB, and in much larger quantities than on the membranes of other parenchymal cells. These are enzymes such as gamma-glutamyltransferase and phosphatase (in particular, glucose-6-phosphatase), catechol-O-methyltransferase, monoamine oxidase, and cytochrome P450 [37] [38] [39] . Due to the high concentration of enzymes in the endothelial cells of the BBB, many substances are metabolized during transport through the cytoplasm of these cells [9] . The height (size in the direction perpendicular to the vessel wall) of the endothelial cell of the BBB is from 3 to 5 microns. (For comparison, the height of enterocytes , intestinal epithelial cells , 17-30 microns) [40]

 
Schematic illustration of tight contact

The ratio of cholesterol to phospholipids in BBB endothelial cells is the same as in peripheral vascular endothelial cells, and is ≈ 0.7 [41] . Passive transport through the BBB cell membranes occurs in the same way as passive diffusion in other endothelial cells [42] . The membranes of endothelial cells contain a large number of channels that are permeable to water molecules. They allow diffusion of water between the brain and the circulatory system [43] .

Due to the absence of fenestrations and a small number of pinocyte vesicles, the endothelial lining of the capillaries of the brain becomes a mechanical barrier to large molecules and foreign substances. In addition, the BBB has a significant electrical resistance - about 1500-2000 Ohms. (For comparison, the electrical resistance for the capillary walls of muscle tissue is only 30 ohms.) [44]

Tight contacts

The endothelial cells of the cerebral vessels are tightly attached to each other. Between their walls, so-called tight contacts are formed, the role of which in providing the BBB is that they prevent various undesirable substances from the bloodstream from entering the brain tissue [45] [46] . Dense contacts between endothelial cells block intercellular (paracellular) passive transport [47] [48] [49] . At the same time, paracellular transport of substances is blocked both from the bloodstream to the brain tissue and in the opposite direction from the brain to the blood [29] .

A large number of transmembrane proteins , such as occludin, various claudins, and switching adhesion molecules bind the lateral portions of the cell walls to each other, participate in the formation of tight contacts and make intercellular transport and metabolism possible [50] . The main proteins that ensure adhesion of endothelial cells and the formation of tight contacts are claudin-5 and claudin-24 [51] . Knockout of the CLDN5 gene responsible for protein synthesis of claudine-5, in experimental mice, resulted in their BBB permeable to molecules with a molar mass up to 800 g / mol. Such genetically modified animals died a few hours after birth [52] .

Basement membrane

 
The basement membrane of the epithelial cell

Endothelial cells completely cover the underlying protein layer, called the basal membrane [31] . The thickness of the basement membrane ranges from 40 to 50 nm. It is visible only under an electron microscope . Consists mainly of type IV collagen , heparin sulfate proteoglycans, laminins , fibronectin and other extracellular matrix proteins . On the brain side, the basement membrane is limited to the plasma membrane of the lamellar endings of astrocyte processes [9] [47] .

Pericytes (podocytes)

 
Electronic microscopic image of pericyte (right) and the lumen of a vessel with three erythrocytes (left)

Pericytes, formerly named after discoverer Charles Marie Benjamin Rouget (1824-1904) by Rouget cells [53] , are part of the BBB [54] . They have several important properties for its functioning: the ability to reduce, regulate endothelium functions and macrophagal activity [55] .

 
Slit cell connections (scheme)

About 20% of the surface of the cerebral capillary endothelial cells are covered with relatively small, oval pericytes. Each 2-4th endothelial cell has contact with a pericyte cell [29] . Mostly pericytes are located at the contact points of endothelial cells [56] [57] . Pericytes are present in almost all arterioles, venules, and capillaries of the body. The level of coverage of the endothelial layer of the capillary by them correlates with the permeability of the vascular wall. In organs and tissues with a permeable vascular wall, they can migrate from the bloodstream to the extracellular space. For example, in the capillaries of the skeletal muscles, the ratio of pericytes: endotheliocytes is 1: 100 [58] [59] .

Pericytes, as well as endotheliocytes, are located on the basement membrane [31] .

Pericytes also synthesize a range of vasoactive substances [59] and play an important role in angiogenesis [60] [61] .

Cell contacts pericyte - endotheliocyte

Pericytes are tightly bound to endotheliocytes. This connection is realized through three types of contacts: gap junctions , focal adhesions and invaginations of the membrane of one cell into the cavity of another [55] . Gap junctions directly bind the cytoplasm of two cells, being permeable to ions and small molecules [62] . With the help of focal adhesions, a strong mechanical connection between the two cell types is realized [63] . Invaginations of the cytoplasm of one cell to another provide both mechanical binding and intercellular metabolism [55] [64] .

Due to close contacts, cells indirectly affect mitotic activity , gene expression and, accordingly, each other's phenotype [60] .

Contractile function

Pericytes contain large amounts of contractile actin protein. Thanks to this structural feature, they are able to alter the lumen of the capillaries and thus regulate local blood pressure [65] [66] .

Macrophage Activity

Данное свойство характерно только для церебральных перицитов. В капиллярной сети мозга они выполняют функцию макрофагов. Соответственно в цитоплазме церебральных перицитов располагается большое количество лизосом . В культуре тканей доказана способность перицитов к фагоцитозу [55] [67] [68] и презентации антигенов [69] [70] .

 
Астроцит (окрашен зелёным) в клеточной культуре

Макрофагальные свойства перицитов образуют «вторую линию защиты мозга» от нейротоксических молекул , которые преодолели барьер эндотелиальных клеток [71] . Таким образом они являются важной составной частью иммунной системы мозга. Сбой макрофагальной активности перицитов может стать одним из факторов развития целого ряда аутоиммунных заболеваний . Имеются данные об опосредованной роли перицитов в развитии болезни Альцгеймера [72] [73] .

Астроциты

 
Взаимоотношение астроцитов и эндотелиоцитов

Астроциты — большие нейроглиальные клетки звёздчатой формы. Своими отростками они выстилают стенки мозговых капилляров со стороны мозговой ткани. В то же время, несмотря на то, что пластинчатыми окончаниями их клеточных отростков выстлано около 99 % капиллярных сосудов, астроциты не выполняют прямой барьерной функции [29] [74] . Астроциты тесно взаимодействуют с эндотелиальными клетками. Между ними осуществляется постоянный обмен веществ [75] . Астроглиальные клетки индуцируют возникновение и формирование ГЭБ. При проведении экспериментов по пересадке сосудов мозга в периферические органы и наоборот — периферических сосудов в ткань головного мозга, отмечено формирование ГЭБ в периферических сосудах, пересаженных в мозг (образование плотных контактов, перестройка эндотелиальных клеток), и разобщение эндотелиальных клеток и появление фенестраций между ними при пересадке мозговых сосудов [23] [76] . Также in vitro показано влияние астроцитов на фенотип эндотелия. В клеточной культуре, содержащей астроциты и эндотелиоциты, отмечено более плотное расположение эндотелия по сравнению с его чистой клеточной культурой [77] .

Астроциты выделяют целый ряд веществ, которые влияют на проницаемость эндотелия [78] . Эндотелиоциты в свою очередь выделяют ингибирующий лейкемию фактор (LIF), цитоки́н интерлейки́н-6 , которые воздействуют на процесс дифференциации астроцитов [78] . Расстояние от пластинчатых окончаний отростков астроцитов до клеток эндотелия и перицитов составляет всего лишь 20 нм [31] [79] .

Главными задачами астроглиальных клеток является обеспечение нейронов питательными веществами и поддержание необходимой концентрации электролитов внеклеточного пространства [78] [80] . Астроциты синтезируют большую часть необходимого клеткам мозга холестерина . Холестерин не проникает через ГЭБ. В то же время в ткани мозга находится 25 % от общего холестерина организма. Бо́льшая его часть входит в состав миелина , который окутывает отростки нейронов аксоны . Нарушения процессов миелинизации нервных волокон вызывают развитие демиелинизирующих заболеваний, в частности рассеянный склероз [81] .

Пластинчатые окончания отростков астроцитов неплотно покрывают со стороны мозга базальную мембрану сосудистой стенки с расположенными на ней эндотелиоцитами и перицитами. За счёт этого между эндотелиоцитами и тканью мозга возможна прямая диффузия различных веществ [78] .

Заболевания, при которых происходит прямое или опосредованное поражение астроцитов (например, болезнь Альцгеймера , астроцитомы ), сопровождаются нарушением функционирования ГЭБ.

Области мозга без ГЭБ

ГЭБ имеется в капиллярах большинства областей мозга, но не во всех. В циркумвентрикулярных органах ГЭБ отсутствует:

  1. Самое заднее поле ( лат. area postrema ) ромбовидной ямки (дна IV желудочка ) — располагается между треугольником блуждающего нерва ( лат. trigonum nervi vagi ) с окаймляющим его самостоятельным канатиком ( лат. funiculus separans ) и бугорком тонкого ядра [82]
  2. Шишковидное тело ( лат. corpus pineale ) (синоним — эпифиз)
  3. Нейрогипофиз
  4. Прикреплённая пластинка ( лат. lamina affixa ) — эмбриональный остаток стенки конечного мозга , покрывающий верхнюю поверхность таламуса . Медиально она истончается, образует извитую пластинку — сосудистую ленту ( лат. tenia choroidea ) [83]
  5. Субфорника́льный орган
  6. Субкомиссура́льный орган

Данная гистологическая особенность имеет своё обоснование. Так например, нейрогипофиз выделяет в кровь гормоны , которые не могут пройти через ГЭБ, а нейроны дна IV желудочка ( лат. area postrema ) улавливают в крови наличие токсических веществ и стимулируют рвотный центр [84] . Защитным барьером соседней с данными образованиями мозговой ткани является скопление таницитов . Они представляют собой клетки эпендимы с плотными контактами [85] .

Мозговой кровоток

В среднем просвет капилляра мозгового сосуда составляет около 40 нм [86] . Наибольшая их плотность отмечена в коре головного мозга — от 300 до 800 капилляров на 1 мм³ ткани [23] .

Суммарная поверхность стенок сосудов мозга составляет 12 м². [87] — 20 [88] Ежеминутно через сосудистую сеть мозга протекает около 610 мл крови со средней скоростью 1 мм/с создавая давление на её стенки 15-35 мм рт. Art. [27] Через капиллярное русло мозга она проходит значительно быстрее (в среднем за 5 секунд), чем в других органах и тканях (для сравнения, в кишечнике , площадь сосудов которого достигает 180 м² среднее время прохождения крови ( англ. mean transit time ) равно 40 часам [89] [90] , а в печени с 70 м² — 30 секундам [91] [92] [93] .

Development

До конца 20-го столетия считалось, что у эмбриона и новорожденных ГЭБ не сформирован в полной степени и соответственно не выполняет своей функции. Причиной этого до сих пор широко распространённого мнения являются недостатки ранее проводившихся физиологических опытов. Эксперименты заключались во введении либо связанных с белками красителей, либо других маркеров взрослым животным и эмбрионам. Первые подобные опыты проводились в 1920 году [94] . Маркеры, вводимые эмбрионам, проникали в ткань мозга и спинномозговую жидкость , в то время как у взрослых животных — нет. В ходе данных экспериментов был допущен ряд методических ошибок (использование чрезмерного объёма вводимого вещества, повышение осмотического давления ), из-за которых происходило частичное повреждение сосудистой стенки и соответственно маркер попадал в ткань мозга [95] [96] [97] . При правильной постановке экспериментов пассажа маркера через сосудистую сеть отмечено не было [98] [99] [100] .

В крови плода в большом количестве содержатся молекулы таких веществ как альбумин , α1-фетопротеин и трансферрин , отсутствуя при этом в межклеточном пространстве ткани мозга [101] . В эмбриональном эндотелии обнаружен транспортёр Р-гликопротеин [102] . Это свидетельствует о наличии ГЭБ в пренатальном периоде . В ходе развития организма происходит дальнейшее совершенствование ГЭБ [101] .

Для небольших поляризованных молекул, например инулина и сахарозы , проницаемость ГЭБ эмбриона и новорожденного значительно выше, чем у взрослых [103] [104] [105] . Схожий эффект отмечен и для ионов [106] . Транспорт аминокислот и инсулина через ГЭБ значительно ускорен, по всей видимости, в связи с большой потребностью в них растущего мозга [107] [108] [109] [110] .

С другой стороны, в мозге эмбриона имеется дополнительный, отсутствующий у взрослых, барьер на границе между ликвором и тканью мозга — так называемые ремневы́е контакты ( англ. Strap Junctions ) между клетками эпендимы [111] .

Evolution

В ходе эволюции нервной ткани позвоночных происходит увеличение её объёма. Бо́льшая масса мозга требует лучшего обеспечения питательными веществами и выведения ненужных и отработанных веществ. Это привело к развитию густой капиллярной сети в ткани мозга. Следующим этапом эволюции стало появление защитного барьера от циркулирующих в крови токсичных для нейронов веществ — ксенобиотиков и токсинов [28] [112] .

У многих беспозвоночных ГЭБ отсутствует. У них эндотелий капилляров нервной ткани не образует сплошной выстилки сосудистой стенки. У высших беспозвоночных — насекомых , ракообразных и головоногих [113] — защитный барьер между нейронами и кровью представлен исключительно глиальной тканью [114] . В этом случае речь идёт о глиальном гематоэнцефалическом барьере [115] .

У всех видов позвоночных имеется ГЭБ, и у большинства из них он образован преимущественно клетками эндотелия сосудистой стенки, скреплёнными между собой плотными контактами. Только у пластиножаберных (среди них акул и скатов ), а также семейства осетровых рыб ГЭБ формируется периваскулярными астроцитами. Из этого следует, что в процессе эволюции, вероятно, происходит расширение функций эндотелиальных клеток сосудов головного мозга, которые перенимают на себя барьерные функции.

Структурные различия глиального и эндотелиального гематоэнцефалических барьеров достаточно велики. Эндотелиальный барьер имеет целый ряд преимуществ. Одним из них является строгое разграничение функций эндотелиальных клеток и клеток астрогли́и, которые обеспечивают гомеостаз внеклеточной среды вещества мозга [114] .

Гемато-ликворный барьер

Кроме гемато-энцефалического барьера существует также гемато-ликворный, который ограничивает центральную нервную систему от кровеносного русла. Он образован эпителиальными клетками с плотными контактами выстилающими сосудистое сплетение желудочков мозга [116] [117] . Гемато-ликворный барьер также имеет свою роль в поддержании гомеостаза мозга. Через него из крови в омывающую мозг спинномозговую жидкость поступают витамины , нуклеотиды и глюкоза . Общий вклад гемато-ликворного барьера в процессы обмена между мозгом и кровью невелик. Суммарная поверхность гемато-ликворного барьера сосудистых сплетений желудочков мозга приблизительно в 5000 раз меньше в сравнении с площадью гемато-энцефалического.

Кроме гематоэнцефалического и гематоликворного барьеров в организме человека существуют гематоплацента́рный , гемато-тестикуля́рный , гемато-клубо́чковый , гемато-ретина́льный , гемато-ти́мусный и гемато-лёгочный барьеры .

Транспорт веществ через ГЭБ

 
Схема транспорта различных веществ через гемато-энцефалический барьер
 
Simple diffusion across the cell membrane

The hemato-encephalic barrier not only detains and does not allow a whole range of substances from the blood to the brain substance, but also performs the opposite function - transports the substances necessary for the metabolism of the brain tissue. Hydrophobic substances and peptides penetrate into the brain either with the help of special transport systems or through the channels of the cell membrane. For most other substances passive diffusion is possible [6] [36] .

Intercellular Transport

In the capillaries of the peripheral organs and tissues, the transport of substances takes place mainly through the fenestration of the vascular wall and the intercellular spaces. Normally, there is no gap between the endothelial cells of the brain vessels. In this connection, nutrients enter the brain only through the cell membrane [118] . Water, glycerin and urea are examples of those small polarized molecules that can freely diffuse through tight junctions between the BBB endothelial cells [119] .

Free diffusion

 
Schematic illustration of the channel of the cell membrane. In the middle there is a molecule of aquaporin forming a channel.

The simplest form of transport through the BBB is free (or passive) diffusion. It can be carried out through the cell membranes of endotheliocytes, as well as through dense intercellular contacts. For diffusion of substances, the driving force is the difference in concentration. Diffusion of substances is proportional to the concentration gradient in the bloodstream and brain tissue. It does not require the cost of cellular energy [120] .

The lipophilic structural elements of the cell membrane, as well as dense cell – cell contacts, reduce the number of substances that can freely diffuse through the BBB. The permeability of the BBB is directly dependent on the lipophilicity of each particular substance [121] .

The permeability of BBB also depends on the molar mass of the substance. Molecules with a mass of more than 500 g / mol cannot diffuse through the BBB. At the same time, the BBB is not a mechanical barrier that freely passes smaller molecules and does not pass larger ones. The process of cell diffusion is dynamic, while it is easier for substances with a molar mass of 200 g / mol than for substances with 450 g / mol [41] [122] . The lipophilic and less substance, the easier it diffuses through the cell membrane [6] .

 
Model of aquaporin - water molecules can freely enter the cell through the center of the protein molecule forming the channel

The German biophysicist Hermann Troible in 1971 put forward a hypothesis about the transport of low-mass molecules across the cell membrane. According to it, they enter the cell through small gaps between the chains of fatty acids of the double layer of the membrane. These gaps are variable, their formation does not require cellular energy [123] [124] [125] [126] . Troibla's theory was spectroscopically proven in 1974 [127] [128] .

The prediction and studies of the permeability of the BBB by one or another substance can be carried out both in vitro [36] [122] [129] [130] [131] and in silico [132] .

Lipophilicity and low molecular weight are not a guarantee of BBB permeability for each specific substance. High-molecular compounds (for example, monoclonal antibodies, recombinant proteins, and others) are retained by BBB [133] .

Tubular permeability

Small polar substances, such as water molecules, can hardly diffuse through the hydrophobic portions of the endothelial cell membrane. Despite this, the high BBB permeability for water has been proven [134] .

In the cell membrane of the endotheliocyte there are special hydrophilic channels - aquapores. In the endothelium of peripheral vessels, they are formed by aquaporin-1 protein (AQP1), the expression of which is inhibited by astrocytes in the blood vessels of the brain [135] . On the surface of the cell membranes of the capillary network of the brain are mainly aquaporin-4 (AQP4) and aquaporin-9 (AQP9) [136] .

The water content in the brain substance is regulated through aquapores. They allow rapid diffusion of water both in the direction of the brain and in the direction of the vascular bed, depending on the osmotic gradient of electrolyte concentrations [137] . For glycerol , urea, and a number of other substances, their own channels, aquaglyceroporins, are formed on the surface of cell membranes. In the BBB, they are represented mainly by aquaporin-9 protein (which also forms aquapores) [138] .

 
Schematic illustration of light diffusion (right) and membrane channel (left)

The process of transport of molecules through specialized channels is carried out faster than active transport with the help of special transporter proteins. At the same time, various biologically active substances can activate or inactivate transport channels located on cell membranes [118] .

Light diffusion

A particular form of diffusion across the cell membrane is facilitated diffusion. A number of substances necessary for the brain, such as glucose and many amino acids, are polar and too large for direct diffusion across the cell membrane. For them, special transport systems are located on the surface of the endotheliocyte cell membranes. For example, for glucose and ascorbic acid (vitamin C) [139], this is a GLUT-1 transporter. Their number on the surface of the vessel turned into the cavity is 4 times more than on the one facing the brain.

In addition to glucose transporters, a variety of protein molecules that perform a similar function for other substances are located on the surface of the endothelium. For example, MCT-1 and MCT-2 are responsible for the transfer of lactate , pyruvate , mevalonic acid , butyrates and acetates . SLC7 transports arginine , lysine and ornithine . The mouse genome contains 307 genes responsible for the synthesis of SLC proteins responsible for facilitated diffusion across the cell membrane of various substances [140] .

Conveyors can transport substances in one or two directions [141] . In contrast to active transport, facilitated diffusion is directed toward the space (intra- or extracellular) with a lower concentration of the substance and does not require the expenditure of cellular energy.

Active transport

 
Removal of substances from the brain tissue into the bloodstream

Unlike passive transport, which does not require energy, an active one consists in the transfer of substances into a space with a higher concentration of a substance and requires a large amount of cellular energy obtained from the breakdown of ATP molecules [118] . With the active transport of substances from the bloodstream to the brain tissue they speak about the influx of the substance ( English Influx ), in the opposite direction - about the outflow ( English Efflux ).

The BBB contains active transporters of enkephalin [142] [143] , antidiuretic hormone [144] , [D-Penicillamine 2, D-Penicillamine 5] enkephalin (DPDPE) [145] .

The first identified EBB transporter [146] is P-glycoprotein, which is encoded by the MDR1 gene. [147] [148]

Subsequently, were discovered, belonging to the class of ABC-transporters English. Multidrug Resistance-Related Proteine (MRP1) [149] , Eng. Breast Cancer Resistance Proteine (BCRP) [150] [151] located mainly on the surface facing the vessel's lumen [152] [153] .

Some Efflux and Influx transporters are stereoselective, that is, only a specific stereoisomer (enantiomer) of a particular substance is transferred. For example, the D-isomer of aspartic acid is a precursor of N-methyl-D-aspartate (NMDA), which affects the secretion of various hormones: luteinizing hormone , testosterone, or oxytocin [154] . L-isomers of aspartic and glutamic acid are stimulating amino acids and their excess is toxic to brain tissue [155] . The ASCT2 efflux transporter ( alanine - serine - cysteine transporter) of the BBB removes the L-isomer of aspartic acid, whose accumulation has a toxic effect, into the bloodstream. Necessary for the formation of the NMDA D-isomer enters the brain using other transport proteins (EAAT, SLC1A3, SLC1A2, SLC1A6) [25] [156] [157] .

In epileptogenic tissue in endothelium and astrocytes, a greater amount of P-glycoprotein protein is present compared to normal brain tissue [158] [159] .

Anion transporters (OAT and OATP) are also located on the endotheliocyte cell membranes [160] [161] . A large number of Efflux transporters remove a number of substances from endothelial cells into the bloodstream [120] .

For many molecules, it is still not clear whether they are derived by active transport (with the cost of cellular energy) or by facilitated diffusion [25] .

Vesicular Transport

Receptor-mediated transcytosis

 
Comparative scheme of phagocytosis , pinocytosis and receptor-mediated endocytosis

With the help of receptor-mediated transcytosis, the transfer of large molecules occurs. On the cell surface facing the vessel lumen there are special receptors for the recognition and binding of certain substances [23] . After contact of the receptor with the target substance, they are bound, the membrane section is invaginated into the cell cavity and an intracellular vesicle, the vesicle, is formed . Then it moves to the surface of the endothelial cell facing the nervous tissue, fuses with it and releases the associated substances. Thus, the transferrin protein of 75.2 kDa [162] consisting of 679 amino acids is transported to the extracellular space of the brain, the low-density lipoproteins forming cholesterol [130] [163] , insulin [164] and other peptide hormones [23] .

Absorption-mediated transcytosis

One of the subspecies of vesicular transport is absorbed-mediated transcytosis. A “sticking” of a number of positively charged substances ( cations ) to a negatively charged cell membrane is noted, with the subsequent formation of a vesicular vesicle and its transfer to the opposite surface of the cell. This type of transport is also called cationic. It passes relatively faster receptor-mediated transcytosis [165] [166] [167] [168] .

Permeability Study

The emergence of a large number of new drugs has made the study of the degree of permeability of the BBB for various substances is extremely important. This applies not only to those drugs that are used in neurology and neurosurgery and whose action directly depends on their ability to overcome the BBB, but also those that are used in other areas of medicine [169] . A number of methods are used to investigate the permeability of the BBB. The classic is to conduct experiments on living organisms ( in vivo ). New advances in science have made possible cell culture experiments ( in vitro ), as well as computer simulation of the process ( in silico ) [170] . The results obtained in mammals ( in vivo ) can be used to describe the BBB permeability for a particular substance in humans.

Physical Basics

To determine the permeability of the BBB by Rankine (1959) and Krone (1965), a model is proposed, which is based on the study of a single capillary. Despite its simplicity, it is close to reality [171] . On the basis of this model, the value of Krone-Rankine is determined, which shows how much of the substance passes through the BBB when passing through the bloodstream of the brain [172] . When its value is less than 0.2 BBB, it is weakly permeable for a substance, and at 0.2-0.8 it is moderately permeable [171] .

In silico studies

The simulation process using a computer is carried out in the earliest phases of the study. The level of free diffusion is calculated, taking into account a number of characteristics of the substance: its lipophilicity, molar mass, amount of hydrogen bonds , etc. [170]

In vitro studies

In vitro experiments are carried out to study transport processes at the cellular level on isolated capillaries [36] . In the course of the experiment, blood vessels are excreted in the experimental animal. It is obligatory to preserve their metabolic activity [173] . Then they are placed between solutions with different concentrations of the studied substances. Molecules can be labeled. The method allows to determine the permeability of the BBB for a particular substance, as well as the processes of its transfer [170] [174] [175] .

In vivo studies

The first to conduct the BBB in vivo was Paul Ehrlich. Experiments on the permeability of certain substances through the BBB are in their direct introduction into the bloodstream, and then determining the content in the brain tissue. According to Walter (F. Walter, 1929), substances used for this purpose must meet the following requirements: distributed in blood and cerebrospinal fluid before their release occurs, not split in the body and not bound to proteins; they should not change the state of the BBB and bring harm to the body [19] . Only when these conditions are met is it possible to determine the BBB permeability for a certain substance in vivo .

Damage to the BBB

Damage to BBB in humans is observed in a number of diseases. Their correction is considered as a therapeutic strategy [176] .

GLUT-1 Protein Deficiency Syndrome

GLUT-1 protein deficiency syndrome (G93.4 according to the WHO International Classification of Diseases [177] ) is a rare autosomal dominant hereditary disease in which there is a violation of GLUT-1 protein synthesis, which is responsible for the BBB permeability to glucose and ascorbic acid . The disease manifests itself in early childhood. The lack of glucose in the brain tissue causes the development of microcephaly , psychomotor disorders, ataxia and a number of other neurological disorders [178] .

Hereditary Folic Acid Malabsorption

Hereditary folic acid malabsorption (D52.8 according to the WHO International Classification of Diseases [177] ) is a rare autosomal recessive hereditary disease, which is marked by a lack of protein synthesis that ensures the permeability of BBB to folic acid.

Alzheimer's Disease

Disruption of the functioning of the BBB in Alzheimer's disease leads to an increase in the amount of amyloid β in the brain. A decrease in the amount of cerebrospinal fluid leads to an increase in the concentration of neurotoxic substances. The neurovascular hypothesis of Alzheimer's disease pathogenesis suggests that the accumulation of amyloid β is also associated with impaired functioning of transporters mediating the transfer of a substance from the brain to the blood, for example, P-glycoprotein and LRP1 . In inflammatory processes, the uptake of amyloid β by pericytes increases , which leads to their death. In addition, in Alzheimer's disease, the efficiency of insulin transport through the BBB, which plays a neuroprotective role, is reduced [176] .

Diabetes mellitus

Diabetes mellitus (E10-E14 according to the WHO International Classification of Diseases [177] ) is a disease in which a variety of functional and structural changes occur in various organs and tissues of the body. There are also significant changes in the BBB, which are manifested in the physicochemical rearrangement of the membrane of endothelial cells and the tight contacts between them [179] .

Multiple Sclerosis

See also Chronic cerebrospinal venous insufficiency.

Multiple sclerosis (G35 according to the WHO International Classification of Diseases [177] ) is a chronic progressive disease of the nervous system, in which myelin protein is predominantly damaged by brain tissue.

The vessels of the brain of healthy people are impermeable to blood cells, including immune cells. In patients with multiple sclerosis, activated T-lymphocytes migrate into the brain parenchyma through the BBB, the level of pro-inflammatory cytokines increases - γ-interferon, TNF-α, IL-1 and others; B-lymphocytes are activated. В результате начинают синтезироваться антитела к белку миелину, что приводит к формированию очагов воспалительной демиелинизации [180] .

Ишемический инсульт

 
Схема миграции лейкоцитов через ГЭБ

Ишемический инсульт (I63 по международной классификации болезней ВОЗ [177] ) — острое нарушение мозгового кровообращения, обусловленное недостаточностью поступления крови к участкам центральной нервной системы.

Ишемический инсульт приводит к высвобождению оксидантов, протеолитических ферментов и цитокинов в ткани мозга, что в итоге вызывает развитие цитотоксического отёка и изменение проницаемости ГЭБ [181] . В результате запускается процесс миграции лейкоцитов через эндотелий в ткань мозга, которые вызывают в том числе поражение здоровых клеток нервной ткани [182] [183] .

Бактериальная инфекция центральной нервной системы

Лишь немногие попадающие в кровь патогенные микроорганизмы способны проникать через ГЭБ. К ним относятся менингококки ( лат. Neisseria meningitidis ), некоторые виды стрептококков — в том числе пневмококки ( лат. Streptococcus pneumoniae ), гемофильная палочка ( лат. Haemophilus influenzae ), листерии , кишечные палочки ( лат. Escherichia coli ) и ряд других. Все они могут вызывать воспалительные изменения как мозга — энцефалит , так и его оболочек — менингит . Точный механизм проникновения этих патогенов через ГЭБ до конца не изучен, однако показано, что воспалительные процессы оказывают влияние на этот механизм [184] . Так, воспаление, вызванное листериями, может привести к тому, что ГЭБ становится проницаемым для данных бактерий. Прикрепившись к эндотелиоцитам капилляров мозга, листерии выделяют целый ряд липополисахаридов и токсинов , которые в свою очередь воздействуют на ГЭБ, делая его проницаемым для лейкоцитов. Проникшие в ткань мозга лейкоциты запускают воспалительный процесс в результате которого ГЭБ пропускает и бактерии [184] .

Пневмококки секретируют фермент группы гемолизинов, который образует поры в эндотелии, через которые и проникает бактериальный агент [185] .

Менингококки и E. coli проникают ГЭБ трансэндотелиально [184] .

Вирусы и ГЭБ

Кроме бактерий, через ГЭБ в ткань мозга могут проникать некоторые вирусы . К ним относятся цитомегаловирус , вирус иммунодефицита человека (ВИЧ) [186] и Т-лимфотропный вирус человека (HTLV-1).

Опухоли головного мозга

Внутримозговые опухоли головного мозга ( глиобластомы , метастазы в мозг и др.) выделяют целый ряд веществ [184] , которые дезинтегрируют работу ГЭБ и нарушают его избирательную проницаемость. Такие повреждения гемато-энцефалического барьера вокруг опухоли может вызвать вазогенный отёк мозга [187] .

Проницаемость ГЭБ для антибактериальных препаратов

ГЭБ избирательно проницаем для различных лекарственных веществ , что учитывается в медицине при назначении препаратов для лечения заболеваний центральной нервной системы (ЦНС). Такие препараты должны проникать в ткань мозга к клеткам-мишеням. Также имеет значение то, что при инфекционно-воспалительных заболеваниях ЦНС проницаемость ГЭБ повышается, и через него могут проходить те вещества, для которых он в нормальном состоянии служил непреодолимой преградой. Особенно актуально это для антибактериальных препаратов.

Проникновение антибактериальных препаратов через ГЭБ [188]

GoodХорошо при воспаленииПлохо даже при воспаленииНе проникают
ИзониазидАзтреонамГентамицинКлиндамицин
ПефлоксацинАмикацинКарбенициллинЛинкомицин
РифампицинАмоксициллинМакролиды
ХлорамфениколАмпициллинНорфлоксацин
Ко-тримоксазолВанкомицинСтрептомицин
МеропенемЛомефлоксацин
Офлоксацин
Цефалоспорины III—IV поколения
Ципрофлоксацин
Левофлоксацин

See also

  • Гистогематический барьер
  • Гемато-офтальмологический барьер
    • Гемато-ретинальный барьер
  • Гемато-тимусный барьер
  • Гемато-тестикулярный барьер
  • Гематоплацентарный барьер

Notes

  1. ↑ Кассиль, 1971 .
  2. ↑ P. Ehrlich. Das Sauerstoff-Bedürfniss des Organismus: Eine Farbenanalytische Studie // August Hirschwald, Berlin (die Habilitationsschrift von Paul Ehrlich). — 1885. — С. 167 .
  3. ↑ P. Ehrlich. Ueber die Beziehungen von chemischer Constitution, Verteilung und Pharmakologischer Wirkung // Gesammelte Arbeiten zur Immunitaetsforschung. August Hirschwald, Ber. — 1904. — С. 574 .
  4. ↑ EE Goldmann. Die äußere und innere Sekretion des gesunden und kranken Organismus im Lichte der vitalen Färbung // Beitr Klin Chirurg. — 1909. — № 64 . — С. 192–265 .
  5. ↑ EE Goldmann. Vitalfärbung am Zentralnervensystem // Abh. K. Preuss. Akad. Wiss. Phys. Med. — 1913. — № 1 . — С. 1–60 .
  6. ↑ 1 2 3 4 5 S. Nobmann. Isolierte Gehirn-Kapillaren als in vitro-Modell der Blut-Hirn Schranke // Диссертация. Гейдельбергский университет им. Рупрехта-Карла . - 2001.
  7. ↑ A. Biedl, R. Kraus. Über eine bisher unbekannte toxische Wirkung der Gallensäuren auf das zentrale Nervensystem // Zentralblatt Innere Medizin. — 1898. — № 19 . — С. 1185–1200 .
  8. ↑ M. Lewandowsky. Zur Lehre von der Cerebrospinal Flüssigkeit // Zentralblatt Klinische Medizin. — 1900. — № 40 . — С. 480–494 .
  9. ↑ 1 2 3 4 BT Hawkins, TP Davis. The blood-brain barrier/neurovascular unit in health and disease // Pharmacol Rev. — 2005. — № 57 . — С. 173–185 .
  10. ↑ 1 2 Constantin von Monakow (1853—1930) and Lina Stern (1878—1968): early explorations of the plexus choroideus and the blood-brain barrier (недоступная ссылка)
  11. ↑ L'Université de Genève «Lina Stern»
  12. ↑ В. Б. Малкин «Трудные годы Лины Штерн»
  13. ↑ L. Stern . Le liquide céphalorachidien au point de vue de ses rapports avec la circulation sanguine et avec les éléments nerveux de l'axe cérébrospinal. Schweiz Arch Neurol Psychiat 11:373—378, 1921; L. Stern, R. Gautier . Recherches sur le liquide céphalo-rachidien I: Rapports enter le liquide céphalorachdien et la circulation sanguine. Arch int Physiol 17:138—192, 1921; L. Stern, R. Gautier . Recherches sur le liquide céphalo-rachidien II: Les rapports enter le liquide céphalorachdien et les élments nerveux de l'axe cérébrospinal. Arch Int Physiol 17:391—448, 1922.
  14. ↑ AA Vein. Lina Stern: Science and fate // Neurologie-Abteilung der Universität Leiden. — 2006.
  15. ↑ Lina Stern
  16. ↑ Die Struktur Der Blut-Hirn- Und Der Blut-Liquor-Schranke — eine Literaturstudie, стр. 6
  17. ↑ L. Stern, E. Rothlin . Effets de l'action directe du curare sur les différentes parties du cervelet. Schweizer Archiv für Neurologie und Psychiatrie 3:234—254, 1918.
  18. ↑ L. Stern, R. Gautier . Recherches sur le liquide céphalo-rachidien III: Arch Intern Physiol 18:403—436, 1923; L. Stern . La barrière hémato-encéphalique dans les conditions normales et dans les conditions pathologiques. Schweiz Arch Neurol Psychiat 13:604—616, 1923.
  19. ↑ 1 2 Гемато-энцефалический барьер // Большая медицинская энциклопедия / Гл. ed. Б. В. Петровский. - 3rd ed. — М.:: Советская энциклопедия, 1977. — Т. V (Гамбузия-Гипотиазид). — С. 127—129. - 576 s.
  20. ↑ JJ Dreifuss, N. Tikhonov «Lina Stern (1878—1968): Physiologin und Biochemikerin, erste Professorin an der Universität Genf und Opfer stalinistischer Prozesse»
  21. ↑ FK Walter. Die allgemeinen Grundlagen des Stoffaustausches zwischen dem Zentralnervensystem und dem übrigen Körper // Arch Psychiatr Nervenkr. — 1930. — № 101 . — С. 195–230 .
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Literature

  • Гемато-энцефалический барьер / Кассиль Г. Н. // Газлифт — Гоголево. — М. : Советская энциклопедия, 1971. — ( Большая советская энциклопедия : [в 30 т.] / гл. ред. А. М. Прохоров ; 1969—1978, т. 6).
  • Штерн Л. С. Гемато-энцефалический барьер. М.—Л.: Биомедгиз, 1935.
  • Майзелис М. Я. Гемато-энцефалический барьер и его регуляция. М.: Медицина, 1961.
  • Кассиль Г. Н. Гемато-энцефалический барьер: Анатомия, физиология. Методы исследования. Клиника. М.: Издательство АН СССР, 1963.

Links

  •   Гемато-энцефалический барьер : тематические медиафайлы на Викискладе
  • Подраздел учебника «Физиология человека» под редакцией В. М. Покровского, Г. Ф. Коротько посвящённый ГЭБ
  • Научно-популярная статья д.м.н. Г.Кассиля о ГЭБ опубликованная в журнале Наука и жизнь в 1986 году
  • Определение и краткое описание ГЭБ Е. В. Трифонова
  • Краткое описание ГЭБ на сайте medbiol.ru
  • Гемато-энцефалический барьер эмбриона данио-рерио , конфокальная фотография , Дженнифер Л. Петерс, Майкл Р. Тэйлор, St. Jude Children's Research Hospital , 2012 г.
  • Открыть ворота гематоэнцефалического барьера Оксана Семячкина-Глушковская, доктор биологических наук, Саратовский государственный университет им. Н. Г. Чернышевского «Наука и жизнь» № 7, 2015
Источник — https://ru.wikipedia.org/w/index.php?title=Гемато-энцефалический_барьер&oldid=98069381


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