The Blood Brain Barrier

Most of the toxicants that enter the nervous system do so by exploiting mechanisms designed to allow entry of essential molecules, such as nutrients, ions, and 

The blood-brain barrier refers to the unique structure and function of CNS capillaries.15,43 Certain substances are not able to pass from the bloodstream into the CNS, despite the fact that these substances are able to pass from the systemic circulation into other 

Several active transport systems also exist on the blood-brain barrier that are responsible for removing drugs and toxins from the brain.6,11 That is, certain drugs can enter the brain easily via diffusion or another process, but these drugs are then rapidly and efficiently transported out of the brain and back into the systemic circulation.6,13 This effect creates an obvious problem because these drugs will not reach therapeutic levels within the CNS, and won t be beneficial. Hence, the blood-brain barrier has many structural and functional characteristics that influence CNS drugs, and researchers continue to explore ways that these characteristics can be modified to ensure adequate drug delivery to the brain and spinal cord.15,23 

The majority of neural connections in the human brain and spinal cord are characterized as chemical 

The blood-brain barrier is a biochemical as well as a physical barrier. Brain endothelial cells create an enzymatic barrier composed of secreted proteases and nucleotidases, as well as intracellular metabolizing enzymes such as cytochrome P-450. Furthermore, y-glutamyl transpeptidase, alkaline phosphatase, and aromatic acid decarboxylase are more prevalent in cerebral microvessels than in nonneuronal capillaries. The efflux transporter P-glycoprotein and other extrusion pumps are present on the membrane surface of endothelial cells, juxtaposed toward the interior of the capillary. Furthermore, CNS endothelial cells display a net negative charge at the interior of the capillaries and at the basement membrane. This provides an additional selective mechanism by impeding passage of anionic molecules across the membrane. 

Basement membrane and Inner endothelial wall are negatively charged 

The brain capillaries are tightly joined and covered by a footlike sheath that arises from astrocytes. Thus, a drug leaving the capillaries in the brain has to traverse not only the nonporous capillary cell wall, but also the membranes of the astrocyte, in order to reach the neurons. Such a structure, frequently referred to as the blood-brain barrier, tends to limit the entry of many drugs into the brain. 

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Concerning the distribution of a drug, models have been published for log BB blood/brain partition coefficient) for CNS-active drugs (CNS, central nervous system) crossing the blood-brain barrier (BBB) [38-45] and binding to human serum albumin (HSA) [46]. 

Specific barriers may serve to limit dmg distribution. The placental barrier is of obvious importance to dmg action in the fetus. Dmg transfers across the placenta primarily by Hpid solubiHty. Hence, this barrier is not particularly restrictive. Similarly, the Hpid solubiHty of a dmg is a primary deterrninant in access to the brain and cerebrospinal fluid. Generally, hydrophilic or charged dmgs can also penetrate to these latter areas, but the result is slow and incomplete. The blood brain barrier is composed of cells having tight junctions which are much less permeable to solutes than are the endotheHal cells of other tissues. 

In other applications of CT, orally administered barium sulfate or a water-soluble iodinated CM is used to opacify the GI tract. Xenon, atomic number 54, exhibits similar x-ray absorption properties to those of iodine. It rapidly diffuses across the blood brain barrier after inhalation to saturate different tissues of brain as a function of its lipid solubility. In preliminary investigations (99), xenon gas inhalation prior to brain CT has provided useful information for evaluations of local cerebral blood flow and cerebral tissue abnormalities. Xenon exhibits an anesthetic effect at high concentrations but otherwise is free of physiological effects because of its nonreactive nature. 

Certain neutral technetium complexes can be used to image cerebral perfusion (Fig. 4). Those in Figure 4a and 4b have been approved for clinical use. Two other complexes (Fig. 4c and 4d) were tested in early clinical trials, but were not developed further. An effective cerebral perfusion agent must first cross the blood brain barrier and then be retained for the period necessary for image acquisition. Tc-bicisate is retained owing to a stereospecific hydrolysis in brain tissue of one of the ester groups to form the anionic complex TcO(ECD) , which does not cross the barrier. This mechanism of retention is termed metaboHc trapping. 

Toxic effects of propranolol are related to its blocking P-adrenoceptor blocking actions. They include cardiac failure, hypotension, hypoglycemia, and bronchospasm. Propranolol is lipophilic and crosses the blood—brain barrier. Complaints of fatigue, lethargy, mental depression, nightmares, hallucinations, and insomnia have been reported. GI side effects include nausea, vomiting, diarrhea, and constipation (1,2). 

A number of quaternary amines are effective at modulating nerve transmissions. They often have the disadvantage of being relatively nonselective and so possess numerous sideeffects. This contrasts with the advantage that they do not cross the blood-brain barrier and so have no central sideeffects. Clo-... 

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

Cancer chemothCTapeutic agents as a rule poorly penetrate the blood brain barrier. Brain tumors are thus not readily treatable by chemotherapy. Diaziquone (at one time known as AZQ) is an exception to this generalization. Treatment of chloranil (213) with the anion from urethane gives intermediate 214, probably by an addition elimination scheme. Displacement of the remaining halogen with aziridine yields diaziquone (215) [.55J. 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

Temozolomide crosses the blood brain barrier and can be used for the treatment of brain tumors (e.g., glioblastoma multiforme). The most common side effects are nausea and vomiting. 

Antidepressants are small heterocyclic molecules entering the circulation after oral administration and passing the blood-brain barrier to bind at numerous specific sites in the brain. They are used for treatment of depression, panic disorders, generalized anxiety disorder, social phobia, obsessive compulsive disorder, and other psychiatric disorders and nonpsychiatric states. 

Local anaesthetics are more consistently effective than other therapies, but their use is controversial. High concentrations are needed for therapeutic benefit, but this also increases the amount crossing the blood brain barrier and entering the brain producing unwanted effects. Topical administration to the airways can reduce this. 

The area postrema is a circumventricular brain region positioned on the dorsal surface of the medulla on the floor of the fourth ventricle. The blood-brain barrier and the cerebrospinal fluid-brain barrier are absent in this region and consequently many substances that do not pass across capillaries in other regions of the brain can do so in the area postrema. The chemoreceptor trigger zone (CTZ), located in the lateral area postrema is sensitive to blood-borne emetogens. Nerves from the CTZ connect with the vomiting centre. 

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

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