The Blood Brain Barrier: An Obstacle for Treatment
The Blood-Brain Barrier: An Obstacle for Treatment
When we have a simple headache, we don’t hesitate to take an aspirin to alleviate the pain. However, suppose we had something much more serious, like a brain tumor. Obviously a Tylenol won’t do the trick, but shouldn’t we just be able to take chemotherapeutic agents and attack the source of the problem? Unfortunately, there are other, literal barriers that prevent chemotherapeutic agents and other drugs from effecting their full force on diseases of the brain.
The blood brain barrier was discovered when dyes were injected into different parts of the human body and observed in the brain. Paul Ehrlich noted that upon injection into the human body, there was no concentration of dye seen in the brain. However, his student (Edwin Goldmann) noted that dye did appear in the brain scans when injected into the cerebral spinal fluid. The scientists realized that there must be some type of separating boundary between the human body and the central nervous system, the blood brain barrier (6). In simplified terms, the blood brain barrier (BBB) is a layer of endothelial cells, which separates the circulatory blood system from the cerebrospinal fluid in the central nervous system (6). There are efflux pumps embedded into the layer of endothelial cells, including the p-glycoprotein pump. This pump will bind to specific toxins and eject that back into the blood stream, preventing them from entering the neurons of the brain (6).
The main purpose of the blood barrier is to block undesirable substances from being able to circulate throughout the central nervous system. The barrier prevents certain bacteria and bacterial infections from entering the brain (6). Also, the barrier serves to facilitate and control the entry of certain substances critical to central nervous system function. By having certain control, it allows the BBB to serve as a center for the homeostasis of the central nervous system and aid in regulating the environment of the brain. It is divided into three different barriers, consisting of the vascular blood barrier, the blood-cerebral spinal fluid barrier, and the blood-retinal barrier. All of these three divisions work in conjunction with one another to establish a space to keep out invading bacteria and macromolecules (4).
Most drugs and substances which do cross the BBB are able to do so with the use of a mechanism called transmembrane diffusion, which allows the drug to meld into the cell membrane and divide into the aqueous environment of the brain’s cellular fluid in order to exert its affect on the brain. Due to solubility rules, only certain drugs are favored for solubility across the membrane. This being the case, substances that are too lipid soluble will not be able to cross, but rather seized by the capillary bed that is part of the barrier. Other factors such as molecular weight of the molecule, charge of the molecule, and the protein binding and structure also influence the ability of a drug to cross from the blood into the BBB (2). For this reason, great care has to be put into the development of drugs that target specific areas of the brain (5). Other mechanisms include the use of membrane vacuoles and extracellular pathways.
There are still conflicted reports of which molecules will be able to cross and which will not. Some reports state the molecule has to be fatty and composed of many hydrocarbon chains, while others state that the drugs must be small and polar, meaning it contains a dipole moment caused by one or more electronegative atoms. For example, relatively large polypeptides seem to cross the BBB, while the entire proteins do not seem to (2).
Some genetic factors may influence how well drugs are able to enter the brain depending on certain people. Interestingly, children respond differently to some different types of drugs. The drug Carmustine is seen in extremely high concentrations in plasma, greater that that seen in adults (6). What structural differences in adult vs. children brains coincide with this difference that is seen in efficacy? Some drugs also vary depending on different ages and genders. Why? These different responses to the drugs could be the result of differences in size and hormone differences between adults and children (7). These differences must be taken into consideration when developing drugs and establishing doses for children versus adults. Different administration techniques may also have an implication in the effectiveness of certain drugs. Differences can be seen depending on oral or IV dispensation, but the compound needs to be transported into the systemic circulation (1).
Overall, mental illnesses are only on the rise. Finding proper therapeutic and pharmaceutical agents to treat these diseases is crucial. Research into the blood brain barrier can certainly aid in this process and allow for better treatment of certain diseases. In addition, the treatment of certain neurological diseases such as Parkinson’s and Alzheimer’s may benefit greatly from the use of more effective drugs, since drugs that are closer to the source may be more likely to help with the problem. Finally, the treatment of brain cancer and brain tumors is crucially reliant on the use and study of drugs that are able to cross the blood brain barrier. This investigation is especially frustrating because drugs that would normally be able to treat tumors effectively are unable to cross the BBB and get to the tumor itself (8). Therefore, normal chemotherapeutic agents are not very successful in treating brain cancers, and these can prove to be extremely fatal as a result. Further investigation into the blood brain barrier and molecules that are able to cross hold enormous implications for research in pharmacology and the treatment of different diseases such as brain cancer and neurodegenerative disorders.
(1) Alavijeh, Mohammad S., Mansoor Chishty, M. Zeeshan Qaiser, and Alan M. Palmer. "Drug Metabolism and Pharmacokinetics, the Blood-Brain Barrier, and Central Nervous System Drug Discovery." NeuroRx 2.4 (2005): 554-71. PubMed. Web.
(2) Banks, William A. "Characteristics of Compounds That Cross the Blood-Brain Barrier." BMC Neurology 9.1 (2009). BioMed. Web.
(4) Gerstner, Elizabeth R., and Robert L. Fine. "Increased Permeability of the Blood-Brain Barrier to Chemotherapy in Metastatic Brain Tumors: Establishing a Treatment Paradigm." Journal of Clinical Oncology 25.16 (2007): 2306-312. PubMed. Web.
(5) McManamy, By John. "The Blood-Brain Barrier." McMan's Depression and Bipolar Web. Web. May 2010. <http://www.mcmanweb.com/blood_brain.html>.
(6) Nerz-Stormes, Maryellen. "Blood Brain Barrier." Message to the author. 15 Apr. 2010. E-mail.
(7) Stevenson, Terrence. "How Children's Responses to Drugs Differ from Adults." British Journal of Clinical Pharmacology 59.6 (2005): 670-73. PubMed. Web.
(8) "THERAPEUTIC TARGETING, BLOOD-BRAIN BARRIER, GENE THERAPY, AND VASCULAR BIOLOGY : National Institute of Neurological Disorders and Stroke (NINDS)." National Institute of Neurological Disorders and Stroke (NINDS). Web. May 2010. <http://www.ninds.nih.gov/find_people/groups/brain_tumor_prg/TherapeuticTargeting.htm>.