Brain fluids interstitial fluid

The brain develops and functions within a strictly controlled environment resulting from the coordinated action of different cellular interfaces located between the blood and the extracellular fluids (interstitial fluid and the cerebrospinal fluid (CSF)) of the brain (Strazielle and Ghersi-Egea, 2013). The barrier between the blood and the brain or spinal cord parenchyma proper, referred to as the BBB, is formed by the endothelium of the cerebral micro vessels. Several layers exist between the blood and brain capillary endothelial cells, a basement membrane consisting of type IV collagen, fibronectin and laminin that completely cover the capillaries, pericytes embedded in the basement membrane, and glia/astrocytes that surroxmd the basement membrane (Figure 49.1). Each of these layers could potentially restrict the movement of solutes (Hawkins et al., 2006 Alvarez et al., 2013). 

FIGURE 29-1. The blood-brain barrier selectively inhibits certain substances from entering the interstitial spaces of the brain and spinal fluid. It is thought that certain cells within the brain form tight junctions that prevent or slow the passage of certain substances. Levodopa passes the blood-brain barrier, whereas dopamine is unable to pass. 

Embedded within the brain are four ventricles or chambers that form a continuous fluid-filled system. In the roof of each of these ventricles is a network of capillaries referred to as the choroid plexus. It is from the choroid plexuses of the two lateral ventricles (one in each cerebral hemisphere) that cerebrospinal fluid (CSF) is primarily derived. Due to the presence of the blood-brain barrier, the selective transport processes of the choroid plexus determine the composition of the CSF. Therefore, the composition of the CSF is markedly different from the composition of the plasma. However, the CSF is in equilibrium with the interstitial fluid of the brain and contributes to the maintenance of a consistent chemical environment for neurons, which serves to optimize their function. 

Cirrito, J. R., May, P. C., O Dell, M. A. et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. /. Neurosci. 23 8844-8853, 2003. 

The brain lacks connection with the lymphatic system. The interstitial fluid drains into the perivascular space, which surrounds arteries and veins, and from there into the sub-arachnoid space where it mixes with the cerebrospinal fluid. This is secreted by the choroid plexuses, which are capillary-rich outgrowths into cavities within the brain, known as ventricles. From the ventricles, cerebrospinal fluid flows through channels to the surface of the brain and... 

The rate at which an equilibrium concentration of a drug is reached in the extracellular fluid of a particular tissue will depend on the tissue s perfusion rate the greater the blood flow the more rapid the distribution of the drug from the plasma into the interstitial fluid. Thus, a drug will appear in the interstitial fluid of liver, kidney, and brain more rapidly than it will in muscle and skin (Table 3.2). The pharmacokinetic concept of volume of distribution (a derived parameter that relates the amount of drug in the body to the plasma concentration) is discussed more fully in Chapter 5. 

The taste cells are situated in the lingual epithelium with the apical membrane exposed to the mucosal surface of the oral cavity and the basal surface in contact with the nerve [interstitial fluid] [FIGURE 10]. Within the basolateral surface are the nerves which respond to the chemestiietic stimulants, i.e. direct nerve stimulation. The microvilli at the apical membrane contain receptor proteins which respond to sweeteners, some bitters and possibly coolants. The olfactory cells are bipolar neurons with dendritic ends containing cilia exposed to the surface and axons linked to the brain, where they synapse in the olfactory bulb. The transfer of information from this initial stimulus-receptor interaction to the brain processing centers involves chentical transduction steps in the membrane and within the receptor cells. The potential chemical interactions at the cell membrane and within the cell are schematically outlined in FIGURE 10. 

As indicated earlier in this chapter, these transporter proteins are found in a variety of cell types but especially in those organs exposed to chemicals from the environment (e.g., gastrointestinal tract), excretory organs (e.g., kidney), and sensitive organs (e.g., brain). The proteins are usually found on the luminal side of epithelial cells in organs of exposure, such as the small intestine, which allows the cells to pump out the potentially hazardous chemical. In sensitive organs such as the brain, the transporters are on that side of cells that will allow chemicals to be pumped back into the blood or interstitial fluid. In organs of excretion, such as the kidney, the transporters are located on the apical side of cells such as the proximal convoluted tubular cells. 

There is a low-protein concentration in the interstitial fluid in the brain. This means that protein binding, which would contribute to a concentration gradient and also assist the transport of non-water-soluble drugs (paracellular), does not occur. 

In addition, the epithelial cells of the choroid plexus facing the cerebrospinal fluid (CSF) constitute the blood-cerebrospinal fluid barrier (BCSFB). The BCSFB is also a significant area for exchange between the blood and the CSF. In rats the total calculated surface area of the choroid plexus is about 33% of that of the BBB [2]. In humans, based on the relative mass of the choroid plexus in comparison with the brain, the relative surface area of the choroid plexus may be in the region of 10% of that of the BBB. The CSF is secreted across the choroid plexus epithelial cells into the brain ventricular system [3] the remainder of the brain extracellular fluid (ECF) and the interstitial fluid (ISF) are secreted at the capillaries of the BBB themselves [4]. The ratio of fluid production from these sites is 40% 60%, respectively [5],... 

The term blood-brain barrier (BBB) refers to the special obstacle that drugs encounter when trying to enter the brain from the circulatory system. The difference between the brain and other tissues and organs is that the capillaries in the brain do not have pores for the free flow of small molecules in the interstitial fluid of the brain. To enter the interstitial fluid, all molecules must cross a membrane. This design is a protective measure to defend the brain from unwanted and potentially hazardous xenobiotics. Traditionally, drugs that target the brain or central nervous system (CNS) cross the BBB by passive diffusion. Transport by carrier proteins across the BBB is becoming better understood but remains an area of active research. 

BBB disruption is associated with significant side-effects including seizures in experimental animals and neuropathologic changes. The mechanism of the neurotoxicity of BBB disruption is not clear, but may be related to the influx of albumin into brain interstitium from the circulation. Albumin is neurotoxic for astrocytes and normally exists at concentrations in brain interstitial fluid that are approximately 1,000-fold lower than the concentrations of albumin in the circulation. This approach is not therefore recommended as an effective strategy for drag delivery to the CNS. 

Transport of water into the cerebrospinal fluid (CSF) and interstitial fluid (ISF) forms the source of the CSF that fills the cerebral ventricles and the subarachnoid spaces around the brain and spinal cord. Early studies by Weed and Cushing identified the CSF as a Third Circulation, functioning along with the fluid between the cells, the ISF, as the lymph of the brain (Weed, 1935,1938). The ISF circulates between the cells and drains into the CSF it is formed osmotically by the extrusion... 

Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid significance for physiology and pathology. Neurochem Int 45 545-552... 

Rosenberg GA, Kyner WT, Estrada E (1980) Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Physiol 238 F42-F49 Rosenberg GA, NavratU M (1997) MetaUoproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 48 921-926... 

The BBB of the brain has two major components. An endothelial layer lies between the arterial blood in the brain capillaries and the interstitial fluid of the brain. In humans, the surface area of the endothelial layer in the brain is approximately 21 square meters [51]. An epithehal layer lies between venous blood and the cerebrospinal fluid (CSF) in the choroid plexus, and has a surface area of only 0.021 square meters in humans [52]. At the spinal cord, the BBB... 

The role of iron in PD is outlined in Figure 21.6. In the brain interstitial fluid, iron is transported bound to transferrin (Tf) which is absorbed by neuronal cells via transferrin receptor (TfRl (-mediated endocytosis. Iron... 

The extracellular space ofthe brain can be divided into two major compartments, the CSF and the interstitial fluid (ISF). The CSF and the ISF are separated from the blood by the choroid plexus or the BCS FB and the brain capillary or BBB, respectively. No anatomical barrier exists between the CSF and the ISF a functional barrier is built up by the flow of CSF from its formation site (choroid plexus) to its absorption site (arachnoid villi) [15]. In the case of a human brain, 20 ml CSF is produced per hour and the complete turnover ofthe total 100 ml CS F occurs approximately within 4—5 h, whereas only 2 ml ISF is renewed per hour compared to the total amount of 300 ml ISF [17, 18]. Neurons are bathed by the extracellular (or interstitial) fluid of the brain (ECF = ISF) that forms the microenvironment ofthe CNS [19]. ISF and CSF are low-protein fluids (plasma CSF ratio 260) due to the tightness of the CNS barrier layers [20] furthermore, the brain has no true lymph or lymphatics. 

The low concentration of protein in the interstitial fluid has been suggested as another factor which may reduce the distribution of some substances in the central nervous system. Lipid soluble compounds, such as methyl mercury which is toxic to the central nervous system (see Chapter 7). can enter the brain readily, the facility being reflected by the partition coefficient. Another example which illustrates the importance of the lipophilicity in the tissue distribution and duration of action of a foreign compound is afforded by a comparison of the drugs thiopental and pentobarbital (figure 3,5). These drugs are very similar in structure, only differing by one atom. Their pKa values are similar and consequently the... 

Guerra, R., Tureen, J.H., Fournier, M.A., Makrides, V., and Tuber, M.G. 1993. Amino Adds in Cerebrospinal and Brain Interstitial Fluid in Experimental Pneumococcal Meningitis. Pediatric Research 33, no. 5 510-513. 

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