School Papers

The dye seen in the brain. However, his

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). 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 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 bloodstream, preventing them from entering the neurons of the brain
(6).

The main purpose
of the blood barrier is to block entry of unwanted toxins into the brain and
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, which Its main distinction is the
tight junctions between cells; together known as the BBB. Endothelial cells
(EC) elsewhere in the body are more permeable to a wider array of molecules.
The blood-cerebral spinal fluid barrier, The Blood-CSF-Barrier with the Choroid
Plexus epithelium which secretes CSF into the cerebral ventricles. Thirdly, the
blood-retinal barrier, also known as the Arachnoid epithelium separating the
blood from the subarachnoid CSF. These three divisions work together with one
another to establish a space to keep out undesirable bacteria and various other
molecules (4).

Most drugs and
substances which do cross the BBB are able to do so with a method called
transmembrane diffusion, which allows the drug to enter the cell membrane and
divide into the aqueous environment of the brain’s cellular fluid in order
affect the brain.  Solubility only allows
certain drugs to cross the membrane. This being the case, substances that are
too lipid soluble will not be able to cross, but rather blocked by the
capillary bed that is part of the barrier. Other factors such as molecular
weight of the molecule, the 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 must 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
conflicting reports of which molecules will be able to cross and which will
not. Some reports state the molecule must 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 tight
junction proteins contribute to the integrity of the barrier. The transmembrane
cadherin proteins are important for the development of tight junctions.
Integral transmembrane tight junction proteins include occludin, claudins,
junctional adhesion molecules (JAMs), endothelial cell-selective adhesion
molecule (ESAM), and the Coxsackie and adenovirus receptor (CAR). Tight
junction proteins that span the gap between cells can be altered in their
localization or cleaved during BBB damage resulting from viral infections.
Viruses such as HIV I invade the brain parenchyma by a ‘Trojan horse’
mechanism, through diapedesis of infected immune cells that either cross the
BBB paracellular or transcellular.

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 than 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 on the effectiveness of certain drugs. Differences can be seen
depending on oral or IV dispensations, but the compound needs to be transported
into the systemic circulation (1).

Finding proper
therapeutic and pharmaceutical drugs to treat diseases such as AD, Stroke, and
Tumors 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 can 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 fatal as a
result. Further investigation into the blood-brain barrier and molecules that
can cross hold enormous implications for research in pharmacology and the
treatment of different diseases such as brain cancer and neurodegenerative
disorders.

Until now the drugs used to treat brain
disorders are very small < 400 Da and highly lipid soluble, most of which treat disorders such as insomnia and depression. Techniques are being developed to treat other diseases such as Alzheimer's and Cancers by opening the BBB thus allowing larger molecules to pass. Two techniques are a Focused ultrasound and Photodynamic therapy. Electron microscopy of animal brain tissue following FUS resulted in trans-endothelial transport by both transcellular and paracellular pathways.  The tight junction-specific proteins show a loss of immunosignals for Occludins & claudin-5. In addition, MR image-guided FUS for the delivery of antibodies and chemotherapeutic agents to the brain has been used on animals. The results were: anti-dopamine D4 receptor antibody, Herceptin and the chemotherapeutic agent, doxorubicin were delivered to specific regions of the animal brain. PDT uses light and a photosensitized chemical to kill tumor cells in the brain. Mainly used neuro-oncology following brain surgery to get rid of any remaining cells. A common photosensitizing drug is 5 aminolevulinic acid (ALA) because it is found to work with PDT. When ALA is used with PDT there is Brain Edema suggesting the weakening of the BBB.