eBriefing

Across the Great Divide

Across the Great Divide
Reported by
Catherine Zandonella

Posted March 13, 2010

Overview

The blood-brain barrier is a sophisticated physical and biochemical sheath separating the blood vessels from the surrounding brain tissue. As researchers learn more about the intricacies of this blood vessel lining, they are fast approaching the ability to move drugs across it to treat brain disorders like stroke, Alzheimer's disease, and even obesity and erectile dysfunction.

Understanding the complexities of the barrier is the key to designing drugs that can cross it, according to four experts on the barrier who spoke at a meeting of the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences on April 26, 2005. Topics discussed included the potential for inhibiting an efflux transporter known as P-glycoprotein to facilitate the transfer of drugs across the blood-brain barrier, the discovery that drugs given intranasally bypass the blood-brain barrier, and how stroke and traumatic injury trigger the destructive proteins known as matrix metalloproteinases (MMPs) to dissolve the blood-brain barrier.

Use the tabs above to view the meeting report and multimedia presentations.

Web Sites

Blood-brain Barrier
This site gives an overview of the anatomy and physiology of the blood-brain barrier.

The Society for Neuroscience
The Society for Neuroscience is a nonprofit membership organization of scientists and physicians who study the brain and nervous system.

The Whole Brain Atlas
Images of the brain in healthy and diseased states.


Books

Begley, D. J., M. W. Bradbury & J. Kreuter, Eds. 2000. The Blood-Brain Barrier and Drug Delivery to the CNS. Dekker, New York.

Couraud, P.-O. & D. Scherman, Eds. 1997. Biology and Physiology of the Blood-Brain Barrier: Transport, Cellular Interactions, and Brain Pathologies. Kluwer Academic Publishers, New York.

Nag, S., Ed. 2003. The Blood-Brain Barrier: Biology and Research Protocols. Humana Press, Totowa, N.J.

Pardridge, W. M., Ed. 2001. Brain Drug Targeting: The Future of Brain Drug Development. Cambridge University Press, New York.

Sharma, H. S. & J. Westman, Eds. 2004. Blood-Spinal Cord and Brain Barriers in Health and Disease. Elsevier Academic Press, Boston.

Zheng, W. & A. Chodobski, Eds. 2005. The Blood-Cerebrospinal Fluid Barrier. Taylor & Francis, London.


Journal Articles

Drug Delivery to the Brain: Using Physiology to Treat Pathology

Banks, W. A. 2005. Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr. Pharm. Des. 11: 973-984.

Banks, W. A. 2004. Are the extracellular pathways a conduit for the delivery of therapeutics to the brain? Curr. Pharm. Des. 10: 1365-1370.

Banks, W. A., S. A. Farr, W. Butt et al. 2001. Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein. J. Pharmacol. Exp. Ther. 297: 1113-1121. Full Text

Jaeger, L. B. & W. A. Banks. 2005. Transport of antisense across the blood-brain barrier. Methods Mol. Med. 106: 237-251

Nonaka, N., S. M. Hileman, S. Shioda et al. 2004. Effects of lipopolysaccharide on leptin transport across the blood-brain barrier. Brain Res. 30: 58-65.

Urayama, A., J. H. Grubb, W. S. Sly & W. A. Banks. 2004. Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier. Proc. Natl. Acad. Sci. U S A. 101: 12658-12663. Full Text

Drug Delivery to Central Nervous System Targets

Chen, C. & G. M. Pollack. 1998. Altered disposition and antinociception of [D-penicillamine(2,5)] enkephalin in mdr1a-gene-deficient mice. J. Pharmacol. Exp. Ther. 287: 545-552. Full Text

Dagenais, C., C. L. Graff & G. M. Pollack. 2004. Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochem. Pharmacol. 67: 269-276.

Graff, C. L. & G. M. Pollack. 2005. Nasal drug administration: potential for targeted central nervous system delivery. J. Pharm. Sci. 94: 1187-1195.

Graff, C. L. & G. M. Pollack. 2005. Functional evidence for P-glycoprotein at the nose-brain barrier. Pharm. Res. 22: 86-93.

Graff, C. L. & G. M. Pollack. 2004. Drug transport at the blood-brain barrier and the choroid plexus. Curr. Drug Metab. 5: 95-108.

Graff, C. L. & G. M. Pollack. 2003. P-glycoprotein attenuates brain uptake of substrates after nasal instillation. Pharm. Res. 20: 1225-1230.

Graff, C. L., R. Zhao & G. M. Pollack. 2005. Pharmacokinetics of substrate uptake and distribution in murine brain after nasal instillation. Pharm. Res. 22: 235-244.

Golden, P. L. & G. M. Pollack. 2003. Blood-brain barrier efflux transport. J. Pharm. Sci. 92: 1739-1753.

Zong, J. & G. M. Pollack. 2003. Modulation of P-glycoprotein transport activity in the mouse blood-brain barrier by rifampin. J. Pharmacol. Exp. Ther. 306: 556-562. Full Text

Intranasal Delivery

Banks, W. A., M. J. During & M. L. Niehoff. 2004. Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration. J. Pharmacol. Exp. Ther. 309: 469-475. Full Text

Benedict, C., M. Hallschmid, A. Hatke et al. 2004. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29: 1326-1334.

Born, J., T. Lange, W. Kern et al. 2002. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 5: 514-516. Full Text

De Rosa, R., A. A. Garcia, C. Braschi et al. 2005. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc. Natl. Acad. Sci. U S A. 102: 3811-3816.

During, M. J., L Cao, D. S. Zuzga et al. 2003. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med. 9: 1173-1179.

Jin, K., L. Xie, J. Childs et al. 2003. Cerebral neurogenesis is induced by intranasal administration of growth factors. Ann. Neurol. 53: 405-409.

Liu, X. F., J. R. Fawcett, L. R. Hanson & W. H. Frey II. 2004. The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats. J. Stroke and Cerebrovascular Diseases 13: 16-23. Full Text

Liu, X. F., J. R. Fawcett, R. G. Thorne et al. 2001. Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. J. Neurol. Sci. 187: 91-97.

Ross, T. M., P. M. Martinez, J. C. Renner et al. 2004. Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J. Neuroimmunol. 151: 66-77.

Schulz, C., K. Paulus & H. Lehnert. 2004. Central nervous and metabolic effects of intranasally applied leptin. Endocrinology 145: 2696-2701. Full Text

Shingaki, T., T. Sakane, S. Yamashita et al. 1999 Transnasal delivery of anticancer drugs to the brain tumors: a new strategy for brain tumor chemotherapy. Drug Deliv. System. 14: 365–371.

Thorne, R. G., G. J. Pronk, V. Padmanabhan & W. H. Frey II. 2004. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127: 481-496.

Wang, F, X. G. Jiang & W. Lu. 2004. Intranasal delivery of methotrexate to the brain in rats bypassing the blood-brain barrier. Drug Delivery Technology 4: 48-55. Full Text

Matrix Metalloproteinases in Acute and Chronic Cerebrovascular Disease

Adair, J. C., J. Charlie, J. E. Dencoff et al. 2004. Measurement of gelatinase B (MMP-9) in the cerebrospinal fluid of patients with vascular dementia and Alzheimer disease. Stroke 35: 159-162. Full Text

Gursoy-Ozdemir Y., J. Qiu, N. Matsuoka et al. 2004. Cortical spreading depression activates and upregulates MMP-9. J. Clin. Invest. 113: 1447-1455. Full Text

Lapchak, P. A., D. F. Chapman & J. A. Zivin. 2000. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 31: 3034-3040. Full Text

Pfefferkorn, T. & G. A. Rosenberg. 2003. Closure of the blood-brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 34: 2025-2030. Full Text

Speakers

William A. Banks, MD

Veterans Affairs Medical Center/St. Louis University
e-mail | web site | publications

William A. Banks is a staff physician and principal investigator at the V.A., St. Louis, and a professor of geriatrics in the department of internal medicine and a professor in the department of pharmacological and physiological sciences. He has authored over 300 non-abstract publications and is on 10 editorial boards, including being editor-in-chief of Current Pharmaceutical Design. He has received numerous awards, and was most recently recognized as the Milton D. Overholser Memorial Lecturer in 2004.

Banks graduated in 1979 with an MD from University of Missouri, Columbia, School of Medicine and trained in internal medicine and endocrinology and metabolism at Tulane University and Veterans Affairs Medical Center, New Orleans. He is board certified in both internal medicine and endocrinology/metabolism. From 1982 to 1985, he was a research associate in the V.A.'s career development program. He remained at the V.A. and Tulane in New Orleans, becoming full professor in the department of medicine before moving to the V.A. and Saint Louis University in 1998.

Gary M. Pollack, PhD

University of North Carolina, Chapel Hill
e-mail | web site | publications

Gary M. Pollack is executive associate dean and professor, School of Pharmacy, the University of North Carolina, Chapel Hill. He received his BA in chemistry and psychology from Knox College in Galesburg, Illinois, and his PhD in pharmaceutics, with a concentration in pharmacokinetics, from the State University of New York at Buffalo. He has been a member of the faculty of the UNC School of Pharmacy since 1984, and served as chair of the school's division of drug delivery and disposition (formerly the division of pharmaceutics) from 1992 through 2004.

Pollack's research is centered on the disposition and action of drugs and toxicants in the central nervous system. His group has made major contributions towards understanding the pharmacokinetics and pharmacodynamics of morphine tolerance, including the key role of nitric oxide in the loss of response to morphine. Most recently, his group has focused on the influence of barrier transporters on blood-brain barrier permeation and intra-organ distribution of substrates, as well as on the pharmacologic activity of opioids. Pollack has mentored more than 40 graduate, undergraduate, and postdoctoral students in his laboratory and has authored over 200 peer-reviewed manuscripts, book chapters, and scientific abstracts. He is a fellow of the American Association of Pharmaceutical Scientists and the American Association for the Advancement of Science, and is associate editor of the Journal of Pharmaceutical Sciences.

William H. Frey II, PhD

Alzheimer’s Research Center, St. Paul
University of Minnesota, Minneapolis
e-mail | web site | publications

William H. Frey II is director of the Alzheimer's Research Center at Regions Hospital in St. Paul, MN, professor of pharmaceutics at the University of Minnesota and consultant to the pharmaceutical and biotechnology industry. His patents, owned by Chiron Corporation and the HealthPartners Research Foundation, target non-invasive delivery of therapeutic and diagnostic agents to the brain and spinal cord for treating neurologic and psychiatric disorders and the use of antioxidants to treat and prevent disease.

Frey earned his PhD in biochemistry at Case Western Reserve University.

Gary A. Rosenberg, MD

University of New Mexico, Albuquerque
e-mail | web site | publications

Gary A. Rosenberg is chairman of neurology and professor of neurology, neurosciences and cell biology and physiology at the University of New Mexico Medical School. He graduated from the Albert Einstein Medical School and did his training in neurology at that institution. His research has focused on the blood-brain barrier and edema. He discovered that the matrix metalloproteinases attack the blood vessels during neuroinflammation. This work has relevance in stroke, multiple sclerosis, and vascular dementia. He is currently studying inhibitors of metalloproteinases, with the goal of identifying therapeutic agents.


Catherine Zandonella

Catherine Zandonella is a science writer based in Princeton, New Jersey, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.