This chapter has described several properties of BBB models along with the advantages and disadvantages of each apparatus or technique. In the future, new and improved models may be invented and contribute to a better understanding of the etiology of both chronic and acute neuro-degenerative brain disorders and disease. In conclusion, an individual cannot clearly define the ideal blood-brain barrier model, since in vivo approaches have obvious pitfalls, and in vitro models are pliable, yet different from in vivo conditions. Given that the ideal model does not exist, caution and skill should be exercised to mimic as closely as possible the specific condition that is to be studied. For example, the use of newborn human cells is a poor model of Alzheimer dementia.
Blood—brain barrier (BBB): A membrane characterized by tight junctions, presence of glia, lack of fenestrations, and minimal pinocytotic vesicles separating the brain tissue from circulating blood and possible harmful substances.
Cell culture: A technique for growing cells outside of the organism in nutrient medium under laboratory conditions.
In vitro: In an artificial environment outside the organism.
In vivo: In an environment inside the organism.
Stem cell: A cell that has the ability to divide (self-replicate) for indefinite periods, often throughout the life of the organism. Under appropriate conditions, stem cells can give rise (differentiate) into many different cell types that compose the organism.
1. Rubin, L. L., and Staddon, J. M. (1999). The cell biology of the blood-brain barrier. Annu. Rev. Neurosci. 22, 11-28. There is an ever-increasing number of review articles on various aspects of blood-brain barrier function. This article will appeal to both the expert and the non-BBB savvy. The main aspects of BBB physiology are clearly outlined and current controversies are addressed in a balanced framework.
2. Schinkel, A. H. (1999). P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev 36, 179-194. This important article describes in detail the molecular and physiologic mechanisms that regulate the passage of xenobiotics into the brain. While a more recent set of review articles has expanded our view on these "gatekeepers," P-glycoprotein remains the archetype molecule on which our knowledge of drug extrusion at the BBB hinges.
3. Hoheisel, D., Nitz, T., Franke, H., Wegener, J., Hakvoort, A., Tilling, T., and Galla, H. J. (1998). Hydrocortisone reinforces the blood-brain properties in a serum free cell culture system. Biochem. Biophys. Res. Commun. 247, 312-315.
4. Stanness, K. A., Westrum, L. E., Fornaciari, E., Mascagni, P., Nelson, J. A., Stenglein, S. G., Myers, T., and Janigro, D. (1997). Morphological and functional characterization of an in vitro blood-brain barrier model. Brain Res. 771, 329-342. Many of the aspects of this minireview are introduced in this early paper describing the advantages of dynamic modeling of the BBB.
5. Yuan, Y., Granger, H. J., Zawieja, D. C., and Chilian, W. M. (1992). Flow modulates coronary venular permeability by a nitric oxide-related mechanism. Am. J. Physiol. 32, H641-H646.
6. Cucullo, L., McAllister, M., Kight, K., Krizanac-Bengez, L., Marroni, M., Mayberg, M., Stanness, K., and Janigro, D. (2002). Anew dynamic in vitro model for the multidimensional study of astrocytes-endothelial cell interactions at the blood-brain barrier. Brain Res. 951, 243.
7. McAllister, M. S., Krizanac-Bengez, L., Macchia, F., Naftalin, R. J., Pedley, K. C., Mayberg, M. R., Marroni, M., Leaman, S., Stanness, K. A., and Janigro, D. (2001). Mechanisms of glucose transport at the blood-brain barrier: An in vitro study. Brain Res. 904, 20-30.
8. Ott, M. J., Olson, J. L., and Ballermann, B. J. (1995). Chronic in vitro flow promotes ultrastructural differentiation of endothelial cells. Endothelium 3, 21-30.
9. Pekny, M., Stanness, K. A., Eliasson, C., Betsholtz, C., and Janigro, D. (1998). Impaired induction of blood-brain barrier properties in aortic endothelial cells by astrocytes from GFAP-deficient mice. Glia 22, 390-400.
10. Krizanac-Bengez, L., Kapural, M., Parkinson, F., Cucullo, L., Hossain, M., Mayberg, M. R., and Janigro, D. (2003). Effects of transient loss of shear stress on blood-brain barrier endothelium: Role of nitric oxide and IL-6. Brain Res. 977, 239-246.
11. Desai, S. Y., Marroni, M., Cucullo, L., Krizanac-Bengez, L., Mayberg, M. R., Hossain, M. T., Grant, G. G., and Janigro, D. (2002). Mechanisms of endothelial survival under shear stress. Endothelium 9, 89-102.
Kerri Hallene, B.S., is a research technologist who has been involved in human and animal studies of the blood-brain barrier in vitro and in situ.
Gabriele Dini, Ph.D., is a biomedical engineer studying various aspects of shear stress and glial involvement in organ models including the blood-brain barrier.
Damir Janigro, Ph.D., is Professor of Molecular Medicine and Director of the Cerebrovascular Center at the Cleveland Clinic Lerner College of Medicine.
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