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19УДК: 599.323.4 (46):531.5:616-084
SOME ASPECTS OF CIRCUMVENTRICULAR SYSTEM
V. S. Pikalyuk \ V.V. Tkach 2, A. O. Romensky 3, L.R. Shaymardanova 4, L.L. Korsunskaya 5
Кафедра нормальной анатомии человека (зав.каф. проф. Пикалюк В.С.), Медицинская академия им. С.И. Георгиевского ФГАОУ ВО «Крымский федеральный университет имени С.И. Вернадского»
Для корреспонденции: 295006, г. Симферополь, бую Ленина 5/7, РФ.
E-mail : pikaluk@ukr.net
1 Пикалюк Василий Степанович, д.м.н., профессор, зав.кафедры нормальной анатомии, Медицинская академия им. С.И. Георгиевского ФГАОУ ВО «Крымский федеральный университет имени С.И. Вернадского»,
2Ткач Вячеслав Владиславович, к.м.н, доцент кафедры нервных болезней, Медицинская академия им. С.И. Георгиевского
3 Роменский Антон Олегович, врач-ординатор к.м.н., ассистент кафедры нервных болезней с курсом неврологии ФПО, Медицинская академия им. С.И. Георгиевского
4Шаймарданова Лейля Рустемовна, к.м.н., доцент кафедры нормальной анатомии, Медицинская академия им. С.И. Георгиевского
5Корсунская Лариса Леонидовна, д.м.н., зав каф. нервных болезней с курсом неврологии ФПО, Медицинская академия им. С.И. Георгиевского
SUMMARY
Circumventricular organs (CVO) were discussed before and were considered qiute specific for their structure and functions. Circumventricular system is represented by brain structures, which are characterized by extensive vascularization and the lack of typical blood-brain barrier, which allows to establish more tight connection between the central nervous system and peripheral blood flow. CVO may be classified into secretory and sensory parts. In addition, they are an integral part of neuro-immune-endocrine regulation.
Key words: Cerebrospinal fluid, brain, blood-brain barrier.
РЕЗЮМЕ
НЕКОТОРЫЕ АСПЕКТЫ ЦИРКУМВЕНТРИКУЛЯРНОЙ СИСТЕМЫ
В. С. Пикалюк, В.В. Ткач, А. О. Роменский, Л.Р. Шаймарданова, Л.Л.Корсунская
Циркумвентрикулярные органы (ЦВО) уже обсуждались ранее и рассматривались как весьма специфичные образования в связи с их строением и функциями. Циркумвентрикулярная система представлена структурами мозга, которые характеризуются интенсивной васкуляризацией и отсутствием типичного гематоэнцефалического барьера, что позволяет установить более тесную связь между центральной нервной системой и периферическим кровотоком. ЦВО можно классифицировать на секреторные и сенсорные структуры. Кроме того, они являются неотъемлемой частью нейро-иммунно-эндокринной регуляции..
Ключевые слова: цереброспинальная жидкость, головной мозг, гематоэнцефалический барьер
The term "Circumventricular system" is closely connected with the development of the doctrine of the structural and functional organization of the blood-tissue barriers in the CNS, especially the brain. The idea of the existence of the barrier between the blood and the brainwas first proposed by Paul Ehrlich in 1885 [1, 2]. By this time, it was known that dyes (e.g., trypan blue) after their introduction into the blood are not found in the brain. In 1913 E. Goldmann has shown that if the dye is injected into the cerebrospinal fluid, the brain is painted [3]. The term "blood-tissue barriers" was suggested by our compatriot L. S. Stern in 1929
[4]. In 1933 Walter and Spats introduced the concept of "blood brain barrier" [5].
The blood-brain barrier (BBB) is a complex heterogeneous system of the brain with multiple levels of selective transport, regulation and protection, capable to maintain homeostasis of the nervous system [6,3].
It is known that the blood-brain barrier is a complex structure consisting of capillaries of somatic type, which is characterized by the presence of an abundance of dense connections with the absence of endocytosis, a three-layered basal membrane, perivascular glial limiting membrane formed by the processes of astrocytes. However, these
processes covering the outer surface of brain capillaries, do not constitute a considerable mechanical obstruction to the penetration of substances into the brain, but they secrete a special substance that increases the density of contacts between the endothelial cells. In the mid- 60s it was discovered the existence of "enzymatic barrier", i.e. enzymes in the tissues lying between the lumen of the capillaries and the neurons of the brain. These enzymes break down substances, which otherwise might penetrate from the blood into the brain. The examples of such "barrier" enzymes are catechol—0— methyltransferase (COMT), monoamine oxidase (MAO), tyrosine hydroxylase and aminopeptidase. Enzymatic barrier mostly prevents the penetration in the brain by monoamines (potentialneurotrans-mitters) than their immediate predecessors [5,6].
So, the BBB consists of at least three main components: tight junctions in the endothelium of capillaries; substances secreted by the processes of astrocytes and supporting the function of tight junctions; "barrier enzymes" [6, 7, 8].
In 1902, Paul Ehrlich noticed that the dyes absorbed by the brain and absorbed by fat tissue, also [9]. As it turned out, fat-soluble substances by using a simple diffusion can pass through the endo-thelial cells [4, 6]. The brain needs certain substances, that can't dissolve in fats, for example, glucose to provide their energy needs, amino acids for protein synthesis. The hydrophilic substances enter the brain with specific proteins—carriers. Now there are famous transport system for: D— glucose; large neutral amino acids; acidic and basic amino acids; electrolytes (K+, Mg2+, Ca2+, I—, etc.); water soluble vitamins; nucleosides, etc. All these systems have common properties: selectivity, stereo specificity, competitive inhibition and saturation [ 10].
However, in the brain there are areas in which, unlike the main mass, the dye trypan blue, injected into mice intravenously, enters into the neurohypo-physis. It was first discovered in 1912 by Shulman [8]. The number of areas with such features, grew gradually. Since all these structures are situated on the periphery of the ventricular system, it was proposed to name them as the circumventricularor-gans.
In the circumventricular organs (CVO), unlike other parts of the brain, the capillaries are fene-strated andtherefore the CVOcan be considered a"gate" into the brain [11]. Here (in CVO) the chemical substances freely leave the lumen of the capillaries and reach the outer boundaries of the ventricles of the brain, where they are detained by close contacts of ependymal cells. This particular organization of the barrier in thecircumventricula-rorgans is often mistaken with the "defects" in the barrier. In reality, the barrier in those regions is not less effective, and the separation is performed not by the endothelium of capillaries, but by the epen-dyma of the ventricles of the brain. Thus, the barrier here islocated just a little further into the brain
tissue, and is called a "blood-liquor barrier". The area of this barrier is 1/5000 of the total area of the BBB [3, 11].
Circumventricular system is represented by brain structures, which are characterized by extensive vascularization and the lack of typical blood-brain barrier, which allows to establishmore tight connection between the central nervous system and peripheral blood flow [12]. In addition, they are an integral part of neuro-immune-endocrine function [4]. The lack of typical blood-brain barrier allows also to consider the CVO as an alternative route for peptides and hormones of the nervous tissue into the blood stream, as well as in the role of "immune guard" of the central nervous system, as these structures play a key role for pathological immune processes during experimental autoimmune ence-phalomyelitis, an animal model of multiple sclerosis [13]. The CVO are classified into sensory and secretory organs.
The sensory organs include the area postre-ma(AP), the subfornical organ (SFO) and the vascular organ of lamina terminalis (VOLT) [13]. They are able to perceive changes in the concentration of substances in blood plasma, and then pass this information to other parts of the brain. Because of this, they provide a direct link of the autonomic nervous system with systemic circulation.
The secretory organs include the subcommis-sural organ (SCO), the posterior pituitary, the pineal gland, the median eminence and the intermediate lobe of the pituitary gland[14]. These bodies are responsible for the secretion of hormones and glycoproteins into the peripheral vascular network, using the principle of feedback in the change of conditions of the brain and/or the action of external stimuli. It's widely discussed if thecho-roid plexuses is a part of CVO. They also have a high concentration of fenestrated capillaries, but the absence of nervous tissue in them and their primary role in the production of cerebrospinal fluid allows to exclude the choroid plexus from CVO [11]. Due to the fact that the pituitary and the pineal gland belong to the endocrine system we are not going to discuss them in this article.The Areapostrema(AP) has structural similarity to the subfornical organ and is located on the surface of the medulla oblongata in the posterior part of the brain, and juts out into the lower-rear portion of the fourth ventricle, lying on both sides of the line connecting the medulla and the spinal cord [15]. Functionally the AP is the central trigger zone for the vomiting reflex. It functions as the main physiological mechanism of the central nervous system for this reaction, which is triggered by the presence of pathological stimuli [16]. The AP also has an integrative relationship with brain areas involved in autonomic control of the cardiovascular and respiratory activities. A recent study showed the presence of the prolactin receptors in the AP [17]. As a result of this study proved the possibility of "direct
contact" prolactin with this brain region. Prolactin is a peptide hormone that in lower animals plays a significant role in osmoregulation by acting on electrolyte balance. In mammals, prolactin also affects reproductive behavior, stimulates lactation. Another recent study showed that introduction of angiotensin II causes a dose-dependent increase in arterial pressure without a significant change in heart rate [18]. The Area postrema also plays a significant role in Parkinson's disease. Drugs that used to treat this disease, have a strong effect on the body, as this part of the brain contains a high density of dopamine receptors. These drugs stimulate dopamine receptors, resulting in, reduced do-pamine concentration and reduced clinical manifestations of Parkinson's disease. However, stimulation of dopamine receptors in the Area postrema activates the vomiting center of the brain, so nausea is one of the most common side effects of anti-Parkinsonian drugs [19]. Since the area of the AP acts as the entry point of information into the brain from sensory neurons of the stomach, intestines, liver, kidneys, heart and other internal organs, it participates in the regulation of important physiological reflexes of the body. The damage of the AP is sometimes called "the central vagotomy", as it greatly reduced the brain's ability to control the physiological state of the body via the vagus nerve [20]. Experiments conducted on rats showed that damage of the AP prevents the detection of lithium chloride, which can become toxic at high concentrations. As a result, rats with the area postrema lesions failed to perform other behavioral and physiological responses associated with the introduction of the toxin and present in the control group, such as lying down on their bellies, delayed stomach emptying, and hypothermia. This experiment emphasizes the importance of not only the AP in the definition of toxic substances in the body, but also in many other physiological responses to the injected toxin [18].
The Subfornical organ (SFO) is located in the terminal plate and extends slightly into the third ventricle of the brain. The SFO can be divided into three anatomic zones: the central zone, consisting solely of glial cells and of the bodies of neurons, rostral and caudal regions,having mainly the nerve fibers [12]. Functionally, however, the SFO can be considered in two parts: the dorsolateral peripheral region and the ventromedial nuclear segment [21]. Participating in critical processes by maintaining the energy and osmotic homeostasis, the SFO has many efferent projections. Indeed, the SFOs neurons have many efferent projections to brain regions involved in the regulation of cardiovascular activities, including the lateral hypothalamus, with fibers ending in supraoptic and paraventricular nuclei and in anteroventral part of the third ventricle with the fibers terminating in the middle preoptic area [22,23]. At the same time, the afferent projections of the SFO are considered less important than the various efferent connection, as
theSubfornicalorgan receives synaptic fibers from the Zonaincerta (uncertain zone) and the arcuate nucleus [24]. The study of anatomy of the SFO is still ongoing, but the latest data showed the presence endothelin(a potent vasoconstrictor) receptors. Finally, it was found that neurons in the SFO are able to maintain the membrane resting potential in the range of -57 to -65 mV [12]. The Subfornical organ is involved into many processes in our body, including but not limited to, osmoregulation, cardiovascular activity and energy homeostasis [23]. It has been proven that hyper-and hypotonic stimuli facilitated the change osmoregulation, demonstrating the fact that the SFO participates in the maintenance of blood pressure. Theactivation of the AT-II receptors in the SFO causes an increase of blood pressure [12]. Additional studies showed that the SFO can be an important intermediary through which leptin acts to maintain the blood pressure within normal physiological limits via descending autonomic pathways associated with cardiovascular regulation [22]. Recent research has focused on the fact that the Subfornical organ is particularly important in the regulation of energy [22]. Observation showed that neurons of the SFO get a wide range of impulses that regulate energy balance. In addition, it is assumed that the SFO is a structure of the brain, capable of constant monitoring of circulating concentrations of glucose. This fact is a further confirmation of the key role of the SFO as a regulator of energy homeostasis.
The Vascular organ of lamina terminalis (VOLT) is located in the anterior wall of the third ventricle of the brain. The VOLT isalso characterized by the presence of afferent projections from the Subfornical organ, the median pre-optic nucleus region, the brainstem and the hypothalamus [3]. Conversely, the vascular organ of the lamina terminalis has the efferent projections to the striamedullaris and basal ganglia. Being one of the most important participant in homeostasis maintenance, the VOLT contains the primary neurons responsible for regulating the osmotic ho-meostasis. These neurons, in turn, have angiotensin receptors, which are used by circulating angioten-sin II to initiate the consumption of water and sodium [11]. In addition to the angiotensin receptors, the neurons of the VOLT are also characterized by the presence of a nonselective cation channel deemed the transient receptor potential vanilloid 1, or TRPV1. It was previously mentioned,that the vascular organ of the lamina terminalis is responsible for maintaining the homeostatic osmolarity of body fluids.
Furthermore, the presence of good vasculariza-tion and fenestrated capillaries allows the glial as-trocytes and neurons of VOLT to perceive a wide range of molecules of blood plasma, the signals which can be converted to other parts of the brain, and, consequently, to cause autonomic and inflammatory responses. In experiments, mammalian VOLT neurons were shown to transduce hyperto-
nicity by the activation of the TRPV1 nonselective cation channels [15]. These channels are highly permeable to calcium and are responsible for membrane depolarization and increased action potential discharge. Stated simply, an increase in os-molarity results in a reversible depolarization of the VOLT neurons. This can be seen through the predominantly excitatory effects of ANG on the VOLT through the TRPV1 receptor. In this context, it is worthy to note the VOLT neurons typically feature a resting membrane potential in the range of -50 to -67 mV [11]. Despite a solid understanding the VOLT role in maintaining homeosta-sis of fluid, the other functions are less clear. For example, it is believed that the VOLT may also play a role in the regulation of secretion luteinizing hormone through a negative feedback mechanism. It is also believed that the VOLT occurs through the initiation of the febrile response in the central nervous system. Finally, the neurons are able to perceive and respond to changes in ambient temperature, indicating its role in adaptation to different climatic conditions [3].
Thesubcommissural organ(SCO) is a small secretory organ that is located near the front entrance of thecerebral aqueductand the median line of the roof of the third ventricle, covering and penetrating the posterior commissure of the brain [25]. Unlike other organs of the circumventricular system the SCO contains a small amount of fenestrated capil-laries,which makes the BBB less permeable [11]. On the other hand, the SCO plays an important role in neuroendocrine regulation, as it contains the secretory function, in part consists of ependymal cells. These ependymocytes are characterized by an elongated cell body covered in cilia, which contains secretory materials. The most prominent of these is the glycoprotein SCO-spondin [26]. When SCO-spondin is released, it travels into the third ventricle, where it aggregates to create Reissner's fibers [14]. The Reissner's fibers are long fibrous projections that travel caudally through the cerebral aqueduct and can terminate as far as the spinal cord. These fibers contribute to the maintenance of the patency of the cerebral aqueduct. If the SCO were to malfunction, causing a loss of the Reiss-ner's fibers, a medical condition known as Congenital Hydrocephalus can develop. Congenital Hy-drocephalus is an ailment characterized by a large and abnormal accumulation of cerebrospinal fluid (CSF) in the brain and is usually caused by genetic mutations [25]. Also, there is evidence that the SCO is involved in the secretion of aldosterone and detoxification processes that use the cerebrospinal fluid, along with osmoregulation. The SCO associated with many systems, but the most closely -with serotonergic one affecting the homeostasis of sodium ions and water. By reducing the amount of fluid a marked decrease in production of Reissner's fibers.This discovery means that SCO and closely associated with it Reissner s fibers are an integral
part of a mechanism to maintain homeostasis of electrolytes and water [14].
The Median eminence (ME) is arranged in the lower part of the hypothalamus ventrally to the third ventricle. It contains many fenestrated capillaries, allowing passage of proteins and neurohormones between the cerebrospinal fluid and peripheral blood flow [27]. The major cell type that makes up the median eminence are specialized ependymal cells known as tanycytes. Tanycytes line the floor of the third ventricle and can be characterized by a singular long projection that delves deep inside the hypothalamus [3]. They were evolutionary related to radial glial cells of the central nervous system. Tanycytes of the Median eminence are frequently found along the fenestrated peripheral capillaries, tightly covering them and forming clusters between the third ventricle and the ME [28]. These clusters can be attributed to tight junctions, which occur between tanycytes in order to restrict the free transport of molecules between the Median eminence and the third ventricle [29]. The ME is also closely linked to the transport of gonadotropin-releasing hormones between the median eminence and the anterior pituitary. Neuronal projections of gonadotropin-releasing hor-monesneurons actually end at the median eminence, allowing for its release into the portal blood system.
Thus, the totality of the organs of the circum-ventricular system, with sensory and secretory functions, is able to ensure the penetration of biologically active substances through the blood-brain barrier, greatly affecting the homeostasis of the brain and the pathogenesis of many physiological reactions ofliving organism.
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