Neurons are arranged in distinctive networks and structures. The environment of neuronal cells is tightly regulated, and any harmful elements must be removed. To this end, the brain has protective mechanisms that separate it from the rest of the body. In addition to structures and functional networks, there is another functional unit in the brain called the neurobarrier [38]. The neurobarrier consists of four different barriers, namely the neuronal and glial membrane barrier, the cerebrospinal fluid-ependyma barrier, the blood-cerebrospinal fluid barrier, and finally the classic BBB. Under physiological conditions, the BBB is impermeable to pathogens. Low vesicular transport by endothelial cells is responsible for maintaining the physiological function of the BBB [39]. The BBB plays an important role in protecting the brain tissue against the uncontrolled influx of toxic substances. Under physiological conditions, the BBB is a diffusion BBB, important for the proper functioning of the central nervous system. In addition, some agents, for instance, oxygen and carbon dioxide, freely diffuse through endothelial cells according to their concentration gradient [40]. Amino acids and glucose pass the BBB by transporters, while larger molecules such as insulin and leptin cross the BBB via receptor-mediated endocytosis [38,41]. In contrast, in various types of neuropathology, many molecules are released in the brain, such as glutamate and aspartate, which cause acute and/or chronic dysfunction of the BBB [2,42,43].

The main structural element of the BBB is the endothelium. In addition to the endothelial cells, the barrier consists of a continuous basement membrane, pericytes embedded in the basement membrane, and astrocytes covering the microvessel from the outside with its own endfeet [44]. In addition, tight junctions between brain microvascular endothelial cells have been documented. The tight junctions and endothelial cells together form the continuous structure of the BBB. The BBB is the gatekeeper between the circulating elements of the blood and the brain tissue. The length of the microvessels of the BBB in the adult brain is about 640 kilometers [45], the total area is about 12 m² and the diameter is 0.3–0.5 µm [46]. Eighty-five percent of the cerebral vessels are made up of capillaries that contain the BBB, which is composed of, among other things, monolayer endothelial cells sealed with tight junctions to ensure low transcellular and paracellular transmission [47]. These vessels are surrounded by a specialized basement membrane, and pericytes in the same basement membrane contribute to the formation of the BBB in the embryo and its maintenance in adulthood. Pericytes are important in terms of the formation and maintenance of tight junctions at the BBB and the control of endothelial transcytosis. The tight junction proteins that make up the BBB are mainly: claudin-1, -3, -5, and -12 and occludin which are attached to the intracellular scaffold via zonula occludens-1, 2, 3. There are studies showing that the loss of pericytes results in the loss of claudin-5, occludin, and zonula occludens-1 or their rearrangement [48,49]. Pericytes have been shown not only to affect tight junctions but also to increase the permeability of the BBB by controlling endothelial passage [50]. The BBB is physiologically equipped with specific transport systems on the side facing the blood and brain. On the luminal side, nutrient transporters and regulatory molecule receptors control the influx of blood elements into the brain parenchyma through the endothelium. On the other hand, reverse transport on the abluminal side removes waste products from the brain parenchyma into circulation [44,51].

Crosstalk between the basement membrane and pericytes, especially astrocytes in the brain forming the BBB, provides contact between blood vessels and neuronal circuits, which causes them to deliver nutrients to brain tissue through this connection [52]. In addition, the water balance and extracellular ions in the BBB are controlled by the water channels and ions that are found in the endfeet of astrocytes [53].

The basal lamina is a layer of extracellular matrix known as the basal membrane, which consists of collagen, laminin, and fibronectin. Astrocytes are found around the cerebral microvessels and control the function of the BBB through astrocyte-derived factors and astrocyte terminal processes called endfeet. The potassium channel, Kir4.1, and aquaporin-4 are located in the endfeet of astrocytes and support BBB function by controlling ionic and water balance to prevent cerebral edema [14,54].

Moreover, in the BBB, astrocytes are converted from a quiescent to a reactive form after injury, and several astrocyte-derived factors induce endothelial cell apoptosis and down-regulate endothelial tight junction proteins, leading to impaired BBB [53]. On top of it, some factors derived from astrocytes may protect endothelial cells and enhance tight junction reassembly, leading to the reconstruction of the BBB [34,55]. In addition, several astrocyte-derived factors also regulate cell adhesion molecules in endothelium and control leukocyte passing [53].