Everett Frost Biochemistry 118Q Final Paper November 30, 2010 The Blood-Brain Barrier and Innovative Technology for Increasing Absorption of Medicine into Brain Tissue Three Blood-Brain Barriers The main blood-brain barrier is a system of zonula occludens that form an impermeable barrier between capillaries that provide blood to the brain and the cerebrospinal fluid in central nervous system itself. This physical barrier is composed of zonula occludens (protein and dimer bonds between endothelial cell layers) between endothelial cells in the central nervous system. The function of this protective layer is to prevent many common bacteria and viruses from entering the brain and causing infection. However, as a result of this protection, many antibiotics and other drugs with physically large crystal structures are also prevented from reaching the brain, making drug delivery difficult. Optimal configurations for passing the blood brain barrier are molecules that weight less than 180 atomic mass units and are significantly liposoluble (that is, their oil/water partition coefficient of 1.6). [3] Other important factors include less than ten hydrogen bonds in water, degree of ionization and plasma protein binding. “Consequently, passive diffusion of drugs across the blood-brain barrier is limited to small, lipophilic compounds, such as benzodiazepines and barbiturates.” [1] The blood brain barrier is important for drug design for this reason, but also because analysis of drugs designed for non-neurological targets can prevent drugs from being toxic to the brain. How does the system of tightly closed capillaries prevent drugs from leaving the bloodstream and entering the brain? There are three main barrier systems that protect the braintissue. There are technically three distinct blood-brain barriers- the first between the bloodstream and the brain interstitial fluid, and the two barriers between the blood and spinal fliud- the choroid plexus epithelial barrier between the blood and cerebrospinal fluid, and the arachnoid epithelium between the bloodstream and subarachnoid cerebrospinal fluid. [3] The endothelial systems in the choroid plexus and the capillaries in the brain are not simply static ‘walls’ that prevent large or unusual molecules from entering the central nervous system, though they do perform that function, rather these are “dynamic tissues that express multiple transporters and drug-metabolizing enzymes.”[1] Neurons and glia also serve in neurovascular units that work in unison to maintain molecular and pumping rate equilibria at the barrier. Astrocytes, also known as astroglia, are glial cells that support the function of the blood brain barrier. These astroglia maintain homeostasis at the barrier and regulate amino acids, neurotransmitters and water transport across the barrier. [6] The second barrier, between the blood and the cerebrospinal fluid, is located within the choroid plexus, in the ventricles of the brain. Physically, endothelial cells also seal off capillaries from the surrounding brain tissue, but the most remarkable defense the choroid plexus has is the production of spinal fluid. The choroid plexus produces about 500 mL of cerebrospinal fluid daily, far in excess of the average brain’s 135 to 150 mL capacity. According to Eyal, Hsiao and Unadkat, this yields a ‘total turnover rate’ of .38% per minute. This rapid flushing of the cerebrospinal fluid back into the blood stream produces a ‘net diffusion gradient’, which decreases the ability of drugs to remain in significant quantities within the brain. Another defense that medication has to contend with is the difference in blood flow to various parts of the brain. Blood flow can vary up to four times between the gray and white matter, causing large variability in concentration and effectiveness of drugs inside the braintissue. Additionally, there is variation in blood flow between areas of the gray and white over time and space, which can be further manipulated by anesthetics, other drugs and conditions within the body. “Thus, a drug that affects regional cerebral blood flow may alter the regional distribution of itself, another drug, or related metabolites, that exhibit “flow limited” kinetics, such as desmethyl-loperamide (Liow et al., 2009).” Another complication related to blood flow is the incomplete protection offered by the blood brain barrier. The endothelial barrier is more permeable in some brain structures and is not present in others. For example, the circumventricular organs, which regulate some sensory and fluid secretion functions, are not protected by the blood brain barrier at all and are exposed to drugs and bacteria in the ‘regular’ bloodstream. Coupled with this initial physical barrier comes the metabolic barrier. This defense consists of enzymes designed to break down bacteria, foreign molecules and endogenous proteins. If a molecule makes it past these enzymes, there are still three types of ‘efflux pumps’ that bind to toxic fat-soluble molecules that have managed to get through the capillary wall. These pumps remove waste products and toxic molecules from the cerebrospinal fluid and return them to the general bloodstream, along with helpful drugs. Besides these factors for removing undesirable compounds from the brain tissue, there are ports located on the luminal and abluminal membranes of endothelial and choroid plexus endothelial cells for amino acids and glucose to cross into the central nervous system, which present possibilities for modified drugs to cross the barrier. “For many drugs, the net transfer across these barriers is determined by interplay between several transport systems which can operate in the same direction or opposite directions.” [1] When designing brain medicines, multiple influx and efflux systems must be taken into account to determine absorption, as well asvariability in diffusion across the three different blood brain barriers. “Differences between the blood brain barrier and the blood cerebrospinal fluid barrier in expression and function of these transporters may contribute to the different pharmacokinetics of drugs in the interstitial fluid, compared to cerebrospinal fluid.” [1] Pharmacokinetics and Drug-Drug Interactions In addition to the three barriers, drug-drug and drug-protein interactions around transport sites also impact the ability of treatments to cross the blood brain barrier. There are a
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