Blood brain barrier methods

Eugenin, E. A., and Berman, J. W. (2003). Chemokine-dependent mechanisms of leukocyte trafficking across a model of the blood-brain barrier. Methods 29, 351-361. 

Vernon H, Clark K, Bressler JP (2011) In vitro models to study the blood brain barrier. Methods Mol Biol 758 153—168... 

Blood-brain barrier permeation of 7, among other drugs, was predicted from its three-dimensional molecular structure by a computational method (0OJMC2204). The combination of molecular topological methods using 137 quinolones, including 7 provided an excellent tool for the design of new... 

Li H, Yap CW, Ung CY, Xue Y, Cao ZW and Chen YZ Effect of selection of molecular descriptors on the prediction of blood-brain barrier penetrating and nonpenetrating agents by statistical learning methods. J Chem Inf Model 2005 45 1376-1384. 

Narayanan R and Gunturi SB. In silico ADME modelling prediction models for blood-brain barrier permeation using a systematic variable selection method. Bioorg Med Chem 2005 13 3017-28. 

One should realize that the intracellular compartment as depicted in Figure 2 represents multiple cell types, whereas in vitro studies normally utilize a single cell type pertinent to characterizing specific attributes of drug transport in that cell system. The method of Shah et al. [51] would be of great benefit to investigating blood-brain barrier transport, consistent with a vascular-extravascular subcompartment brain model. 

Clark, D. E., Prediction of intestinal absorption and blood-brain barrier penetration by computational methods, Comb. Chem. High Throughput Screen., 2001, 4, 477—496. 

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... 

The rather time- and cost-expensive preparation of primary brain microvessel endothelial cells, as well as the limited number of experiments which can be performed with intact brain capillaries, has led to an attempt to predict the blood-brain barrier permeability of new chemical entities in silico. Artificial neural networks have been developed to predict the ratios of the steady-state concentrations of drugs in the brain to those of the blood from their structural parameters [117, 118]. A summary of the current efforts is given in Chap. 25. Quantitative structure-property relationship models based on in vivo blood-brain permeation data and systematic variable selection methods led to success rates of prediction of over 80% for barrier permeant and nonper-meant compounds, thus offering a tool for virtual screening of substances of interest [119]. 

Franke H, Gallah HJ, Beuckmann CT (2000) Primary cultures of brain microvessel endothelial cells A valid and flexible method to study drug transport through the blood-brain barrier in vitro. Brain Res Prot 5 248-256... 

Seelig A, Gottschlich R, Devant RM (1994) A method to determine the ability of drugs to diffuse through the blood-brain barrier. Proc Natl Acad Sci USA 91 68-72. 

Distribution of drugs is restricted in two areas the brain and the placenta. Refer to Exhibit 5.3 for a brief description on how drugs cross these barriers. Exhibit 5.4 presents a potential new method to deliver drugs across the blood-brain barrier. 

Figure 7. A serotonergic synapse including a depiction of the acute tryptophan depletion method discussed in the text. All large neutral amino acids (SLNAAs) share a common blood-brain barrier transporter. The serotonergic precursor, tryptophan, essentially competes with the other LNAAs for transport. Thus tryptophan is uniquely susceptible to acute dietary manipulation. Numerous serotonergic receptor types exist, including presynaptic S-HTm and (somatodendritic) 5-HTia autoreceptors and postsynaptic 5-HTia, 5-HTid, 5-HT2a 5-HT2c 5-HT3 and 5-HT4 receptors. Additional modulation of serotonin activity can occur via the action of selective serotonin re-uptake inhibitors (SSRls) including fluoxetine, fluvoxamine, and citalopram.

Brain Studies. Rubidium-82 has also been used to study blood brain barrier changes in patients with brain tumors or Alzheimer s type senile dementia (28-30). The method of study is similar to the heart studies without gating. Figure 11 shows the uptake of Rb-82 in the three levels of a brain tumor. This non-invasive procedure provides information on the size and vascularity of the tumor. In the slice OM + 10 there is a vascular rim and a necrotic center in the tumor. The metabolism of glucose was determined in the same tumor patient using F-fluorodeoxyglucose produced on a cyclotron and the results correlated well with Rb-82 distribution. 

Method for increasing blood-brain barrier permeability by administering a bradykinin agonist of blood-brain barrier permeability. Alkermes, Inc., Cambridge, MA. U.S. Patent 5112596, issued 5-12-92. 

The trials described so far have commonly shown a lack of usefulness of NKi receptor antagonists in the treatment of pain. But we do not know whether the failure of the selected compounds is a matter of pharmacodynamics (e.g. poor penetration of the blood brain barrier) or a genuine discrepancy between animal and human pain pathophysiology (Urban and Fox, 2000). Hence, animal tests should carefully be chosen whether they are predictive or not, and it would be helpful if a wider range of conditions could be examined (Hill, 2000a). Therefore, new preclinical analysis methods should be developed for a more effective judgement of likely clinical outcomes. 

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