Blood-brain barrier cells

Kniesel U, Wolburg H. Tight junctions of the blood-brain barrier. Cell Mol Neu-robiol 2000 20 57-76. 

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... 

Carl SM, Lindley DJ, Couraud PO, Weksler BB, Romero I, Mowery SA et al (2010) ABC and SLC transporter expression and Pot substrate characterization across the human CMEC/D3 blood-brain barrier cell line. Mol Pharm 7 1057-1068... 

Owe-Young R, Webster NL, Mukhtar M, Pomerantz RJ, Smythe G, Walker D, Armati PJ, Crowe SM, Brew BJ (2008) Kynurenine pathway metabolism in human blood-brain-barrier cells implications for immune tolerance neurotoxicity. J Neurochem 105 1346-1357... 

Krizbai, I.A., Deli, M.A., 2003. Signaling pathways regulating the tight junction permeability in the blood-brain barrier. Cell Mol. Biol. (Noisy-le-grand) 49,... 

Lawrenson JG, Reid AR, Allt G, 1997. Molecular characteristics of pial microvessels of the rat optic nerve. Can pial microvessels be used as a model for the blood-brain barrier Cell Tissue Res. 288, 259-65. 

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. 

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. 

Extrahypothalamic OX-B-like immunoreactivity, reminiscent to that of CRF, has been described in clustered GABAergic neuronal populations, in the lateral division of central nucleus ofthe amygdala, the bednucleus of the stria terminalis, and in the hippocampus. Moreover, ectopic expression of preproorexin mRNA in the gut, ependymal cells, neuroblastomas, and of orexin receptors in adrenal gland, cancer and hematopietic stem cells suggests yet unexplored roles of orexins as paracrine factors controlling blood-brain barrier, and tumor or stem cell function. 

The symptoms of parkinsonism are caused by a depletion of dopamine in the CNS. Dopamine, when given orally, does not cross the blood-brain barrier and therefore is ineffective The body s blood-brain barrier is a mesh-work of tightly packed cells in die walls of the brain s capillaries that screen out certain substances. This unique meshwork of cells in the CNS prohibits large and potentially harmful molecules from crossing into die brain. This ability to screen out certain substances lias important implications for drug dierapy because some drugs are able to pass through die blood-brain barrier more easily dian odiers. 

Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross die blood-brain barrier, and a small amount is dien converted to dopamine. This allows the drug to have a pharmacologic effect in patients witii Parkinson s disease (Pig. 29-1). Combining levodopa witii another drug (carbidopa) causes more levodopa to reach die brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone. Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa Sinemet CR is a time-released version of die combined drugs). 

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. 

Proteases are crucial enzymes induced by HIV to alter the physiology of the central nervous system. Indeed, proteases participate in brain infection, helping infected peripheral cells to cross the blood-brain barrier, as well as in the viral neuropathogenesis as will be later discussed. We will first describe examples of... 

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