BBB cells

CPT-cAMP, RO-20-1724, and 0.1 aM dexamethasone, TEER increased to 85 0 cm. This effect on TEER was neither observed without astrocytes, nor with other sources of astrocytes (see Note 2). In these conditions, the human BBB model was also sensitive to DT (determined as described earlier) and lipopolysaccharide (EPS, as described in ref. [9]). We were, however, unable to find any indication of P-glycoprotein (P-gp) expression in these cells (determined as described in ref [7]). The relatively low TEER across the BBB model and the possible absence of P-gp expression, however, limits the appUcabitity of this constellation of human endothelial cells and rat astrocytes as a BBB cell culture model for the use for drug transport and effect screening purposes. 

Figure 5 Scheme describing interactions between the BBB cells and four major groups of Puronics . (From Ref. 58.)... 

Pluronics (group II). Therefore, the extremely hpophihc Pluro-nic cause less energy depletion and, consequently, have less effect on Pgp efflux system in BBB cells than the intermediate block copolymers. An additional consideration with the very lipophihc Plm onic compositions is the low CMC. It has heen shown previously that the effect of Pluronic is mediated hy the copolymer single chain imimers, rather than hy the micelles (74). Extremely lipophihc Plm onic tend to form micelles at low concentrations of the copolymer in water solutions. Thus, the micelle formation decreases the ability of Pluronic molecules to enter the cells and reduces the influence of the copoljrmer on all systems in the barrier cells. All in all, a delicate balance between hydrophihc and lipophihc components in the Pluronic molecule shoffld be accomplished to provide the best interactions and the most significant impact of the block copolymer on the endothelial cell transport. 

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. 

Excellent biological arguments exist for a direct impact of fever specifically on neurological outcome. On a local level, fever produces increased levels of excitatory amino acids (e.g., glutamate and dopamine), free radicals, lactic acid, and pyr-uvate. There is an increase in cell depolarizations and BBB breakdown. Enzymatic function is impaired and cytoskeletal stability reduced. These events lead to increased cerebral edema, with a possible reduction in CPP as well as larger volumes of ischemic injury. " ... 

The in vitro measurements of permeability by the cultured-cell or PAMPA model underestimate true membrane permeability, because of the UWL, which ranges in thickness from 1500 to 2500 pm. The corresponding in vivo value is 30-100 pm in the GIT and nil in the BBB (Table 7.22). The consequence of this is that highly permeable molecules are (aqueous) diffusion limited in the in vitro assays, whereas the membrane-limited permeation is operative in the in vivo case. Correcting the in vitro data for the UWL effect is important for both GIT and BBB absorption modeling. 

Kramer, S. D. Begley, D. J. Abbott, N. J., Relevance of cell membrane hpid composition to blood-brain barrier function Lipids and fatty acids of different BBB models, Am. Assoc. Pharm. Sci. Ann. Mtg., 1999. 

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