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Introduction: Scientists have revealed by different experiments that

Introduction: In human body, the Central nervous system CNS is a precarious and responsive system. For the efficient working of CNS, it is important to maintain the homeostatic balance within it. (1)(2)The balance is regulated by Blood brain barrier, which separates the CNS and peripheral system of circulation to maintain the balance of different substances like ions, macromolecules, essential nutrients to brain and neurotoxins.(3) In the history, firstly Paul Ehrlich gave prove for existence of BBB by his experiment. (4) He observed that hydrophilic dye used during his experiment, stains all parts of body except brain.(8) The experiments of Ehrlich and other scientists gave insight that BBB block the transport of materials across the brain.(9) The studies reveal that there are different types of barriers other than blood brain barrier to maintain the balance in CNS. The BBB confinement of the substances is variable in different parts of CNS. (10)Composition of blood brain barrier:The CNS endothelial cells (single cell forming sheath around a capillary) play main role in maintaining the BBB, but BBB is established anatomically and physiologically by different components which include Neurovascular unit, transporters and junctions around the CNS endothelial cells. (5)(6)(7) ? Neurovascular unitIn past, it was thought that it is the only ability of endothelial cells of brain to work for maintaining the BBB. Scientists have revealed by different experiments that there are different type of cells which are involved in maintaining BBB, most important of them are astrocytes and pericytes. (11)• Astrocytes: Astrocytes are the cells present in close proximity to endothelial cells. Studies showed that mainly there are two types of astrocytes. One of them is protoplasmic form, which reside in gray matter. The processes of this type of astrocytes possess very fine branching which surrounds the cell evenly. Protoplasmic astrocytes along with other functions, also contribute to BBB regulation. Second type is fibrous astrocytes, found in white matter of CNS. They are limited in number, but they are long and function to support the axon structurally. (12)(13)The role of astrocytes is very diverse extending from regulation of neurotransmission to water content in brain. (14)(15) Astrocytes also responsible for discharge of glutathione which perform antioxidant function. They regulate the permeation in BBB by influencing the tight junctions. (16)• Pericytes: These structures are present near to blood vessels and they enclose the walls of blood capillaries of brain. The number of pericytes in peripheral vessels is limited in contrast of brain vasculature. (17) The presence of proteins which are involved in contraction of cytoskeleton attributed the pericytes role in regulation of blood flow. (18) Pericytes are also involved in discharge of proteins which regulate functions of tight junctions. (17)• Microglia: The microglias are perivascular to CNS micro vessels. There are two states of microglia in which it actively performed its function. These functions include discharge of pro inflammatory cytokines, tissue necrosis factor, vascular endothelial growth factor and also involved in repairment of tissues. (19) They are often triggered by endothelial cells. The microglia cells play their role in defensive mechanism for immunity. (20)• Basement membrane: It is also a main part of neurovascular unit. It is responsible for interaction of astrocytes, pericytes and neurons with one another. The loss in its functionality can lead to disturbance of BBB and consequently increase in permeability of substances to brain. (21)• Neurons: The microvasculature of brain is also surrounded by different types of neurons which not only work for regulation of blood flow to these micro vessels but also involved for maintenance of the restricted permeability of BBB. (22)? JunctionsThe BBB is maintained by different types of junctions which work along the neurovascular unit for effective restriction of BBB. (23) Mainly there are two major types of junctions which are present between endothelial cells; Adherent junction and tight junctions. (24)• Adherent junctions: The adherent junctions comprise of different types of proteins. Cadherins are the proteins which mainly perform their function in maintaining BBB. The Cadherin proteins include VE-cadherin, encompassing area between the cells. These cadherins are associated to ?, ? and ? catenins. (24) This type of junction is responsible to grip the endothelial cells firmly. Other than that, these junctions restrict the interaction of cells during growth process of micro vessels and also maintain the asymmetric organization of different cellular components. (25) • Tight junctions:  These junctions are present on the apical portion of endothelial cells providing with an electrical resistance of ? 1800 ?/cm2. (26) The main components of tight junctions are occludins, claudins and junctional adhesion molecules. These components are further linked to several other protiens like zonula occludens and work together for maintaining the tightness of BBB. (24) Tight junctions perform their function by inhibiting the diffusion of ions and large molecules between the cells. (27)? Transporters

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