Blood-brain barrier characteristics

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. 

Stewart PA, Wiley MJ. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells a study using quail-chick transplantation chimeras. Dev Biol 1981 84 183-192. 

Krum JM, Kenyon KL, Rosenstein JM. Expression of blood-brain barrier characteristics following neuronal loss and astroglial damage after administration of anti-thy-1 immunotoxin. Exp Neurol 1997 146 33-45. 

The cerebral endothelial cells of the blood-brain barrier originate from the middle germinal sheet of the embryo, the mesoderm [17]. Concomitant with migration and proliferation of capillary endothelial cells during formation of the cerebral vascular network occurs the imprinting of the cells. Thereby, induction by the cellular surrounding plays an important role [18-21], The relevance of the cellular environment for the development of the barrier function of cerebral microvessels was first demonstrated by Stewart and Wiley [22], who transplanted embryonic brain tissue of a quail into embryonic gut tissue of chicken and vice versa. The cerebral transplant was vascularized by intestinal vessels, in which properties of the blood-brain barrier had been induced. In transplanted brain vessels, however, no characteristics of a barrier could be demonstrated, due to the lack of a neuronal environment. These results indicated that the cerebral microvessels are of extraneuronal origin, with properties that are induced by the cellular environment. In addition, brain tissue has the capability to induce blood-brain barrier characteristics also in noncerebral vascular tissue [23],... 

At the inner border of ONH, the ILM becomes continuous with the basement membrane of fibrous astrocytes lining the internal surface of the ONH [21]. However, the lateral borders between the ONH and the adjacent choroid and retina are not well defined. Furthermore, it was reported [49] that micro vessels in the prelaminar region of the ONH lack classical blood-brain barrier characteristics and display nonspecific permeability, possibly mediated by vesicular transport. Thus, there is a theoretical possibility that topically applied drugs can penetrate indirectly through the retrobulbar space and then, through the ONH, reach the posterior choroid and retina. It was reported that following retrobulbar administration of fluorescein, the dye rapidly accumulated in the ONH and penetrated later to the vitreous [50],... 

Neuhaus, J., W. Risau, and H. Wolburg. 1991. Induction of blood-brain barrier characteristics in bovine brain endothelial cells by rat astroglial cells in transfilter coculture. Ann N Y Acad Sci 633 578. 

Meyer J, Mischeck U, Veyhl M, Henzel K, Gaba HJ, 1990. Blood-brain barrier characteristic enzymatic properties in cultured brain capibary endothebal cebs. Brain Res. 514(2) 305. 

Molecular structure has been shown to influence absorption. By examining the structural characteristics of drugs that were in use, certain common characteristics of well-absorbed molecules were identified, commonly referred to as the rule of five. Some investigators have used this as a basis for characterizing the drug-likeness of a lead chemical. Other factors also come into play including receptor activity, metabolism profile and for CNS-active compounds, an ability to cross the blood-brain barrier. 

ACT-078573 (20) is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, 0X1 and 0X2 [61]. In animal models, the administration of 20 resulted in a dose-dependent decrease in alertness and increased non-REM and REM sleep. The compound, administered at oral doses ranging from 10 to 300 mg/kg, dose-dependently decreased alertness in rats and exhibited increased duration of REM and non-REM sleep, indicating no intrusive REM sleep that is characteristic of narcolepsy. In dogs, treatment with 20 (10-100 mg/kg p.o.) resulted in dose-dependent reductions in mobility and also induced signs of clinical somnolence. 

The blood-brain barrier forms the interface between the bloodstream and the brain parenchyma and thus controls the passage of endogenous substances and xenobiotics into and out of the central nervous system. Brain microvessels exhibit a variety of unique structural features, such as an extremely tight endothelium without fenestration, a very low rate of pinocytosis, tight junctions between endothelial cells excluding paracellular permeability, and a series of polarized transport proteins. The following chapter describes the structural and functional characteristics of the blood-brain barrier with emphasis on transport proteins, as well as in vitro techniques, which allow studying this complex barrier in the brain. 

In vitro models mimicking the characteristics of the blood-brain barrier in a realistic manner provide a broad field of application in experimental, pharmaceutical, and clinical studies. In contrast to in vivo studies, which are mainly... 

Freshly isolated or subcultured brain microvascular endothelial cells offer a notable in vitro tool to study drug transport across the blood-brain barrier. Cells can be grown to monolayers on culture plates or permeable membrane supports. The cells retain the major characteristics of brain endothelial cells in vivo, such as the morphology, specific biochemical markers of the blood-brain barrier, and the intercellular tight junctional network. Examples of these markers are y-glutamyl transpeptidase, alkaline phosphatase, von-Willebrandt factor-related antigen, and ZO-1 tight junctional protein. The methods of... 

Ghazanfari FA, Stewart RR (2001) Characteristics of endothehal cells derived from the blood-brain barrier and of astrocytes in culture. Brain Res 890 49-65... 

Structural and theoretical chemistry studies of phenytoin and carbamazepine suggest that they bind to the Na+ channel via a pharmacophore that consists of an aromatic ring and an amide linkage. This pharmacophore consists of two of the three structural features found in local anesthetics. The ionizable group, which is characteristic of local anesthetics, precludes the ability to diffuse across the blood-brain barrier. 

In individuals with PKU, a secondary, normally little-used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate (Fig. 18-25). Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name phenylketonuria. Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites. 

The brain has no significant stores of triacylglycerol, and the oxidation of fatty acids obtained from blood makes little contribution to energy production because fatty acids do not efficiently cross the blood-brain barrier. The intertissue exchanges characteristic of the absorptive period are summarized in Figure 24.8. 

Manganism, the result of overexposure to manganese, primarily affects the brain [23]. Severe psychiatric symptoms including hyperirritability, violent acts, and hallucinations are characteristic of manganism. These symptoms manifest themselves due to the ability of manganese(II) to cross the blood-brain barrier [24]. Manganese(II) ions also interfere with the calcium channels of cardiac cells, which leads to decreased ability of the heart muscle to contract [25]. This results in a decrease in heart rate, an increase in aortic pressure and ventricular fibrillation [25,26]. Manganese has been found to interfere with DNA replication and has been shown to increase the occurrence of cancer [27]. 

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... 

As of today, there are no commercially available pharmaceutical products of this technology. The pharmaceutical industry however, is involved in developing nanoparticle-based delivery systems. Use of nanospheres to modify the blood-brain barrier (BBB)—limiting characteristics of the drug enables targeted brain delivery via BBB transporters and provides a sustained release in brain tissue and vaccine delivery systems to deliver therapeutic protein antigens into the potent immune cells are under investigation.103... 

---