Keira Ramirez Biochemistry 02/1/2012

The Blood Brain Barrier

The Blood Brain Barrier is anatomically produced by specialized blood vessels. All blood vessels are made of a basal membrane and surrounding endothelial cells. Throughout the body endothelial cells are fenestrated meaning that they have large openings between blood cells which allow big molecules or polarized molecules to move freely through and from the blood into surrounding tissue. This is important because the blood stream supplies our body with necessary nutrients and sugars. However there is a danger of poisons, toxins, and heavy metals which can thus get into our tissue through the fenestrated endothelial cells. This is bad for organs such as the liver and kidney, not to mention the brain. In fact, it would be drastically worse for the brain than for any other organs. Because, in the brain nerve cells are not constantly regenerated as in the rest of the body, meaning that we are stuck with the same brains cells with which we are born for our entire life span. With the conclusion that if they are poisoned once, they are gone forever, bringing with them the function associated with these cells. Why is the brain so special and doesnt regenerate like, for example skin? The brain is extremely complex. In the brain it matters which cell is connected to other cells. There are trillions of very very specific connections to very specific nerve cells in particular sections of the brain. When cells are lost it is impossible for another cell to be regenerated with the right partners and right strength of connection. In some cases bad connections could be worse than no connection at all. That is why, simpler animals, like goldfish, can regenerate brain cells where we can not. For all these reasons the brain needs to be protected. And that is what the Blood Brain Barrier is for.

The Blood Brain Barrier does this with specialized blood vessels. In these blood vessels the endothelial cells are tightly sealed by tight junctions. Tight junctions are very helpful in keeping out dangerous molecules and toxins, the only problem is, how does the brain receive the nutrients and other necessities necessary, through these blood vessels? The brain needs more nutrients and energy than any other organ in our body and to get them the brain has specialized proteins that can transport molecules into the brain tissue, or that can open gates so that ions or polar substances are able to flow into the brain. However, what I just described is not true for all bigger molecules because the biochemistry between molecules dictates what molecules can flow through the membrane of the endothelial cell into the membrane of the brain cell. Because, while the tight junctions can avoid molecules from traveling into those holes a molecule that is hydrophobic can simply diffuse through the lipid membrane and does not need an opening. All cells are surrounded by lipid bilayers, which are composed of phospholipids that have a polar phosphate group as a head (a polar cap) and two hydrophobic chains, consisting of many carbohydrate bonds. Because the blood and the internal milieu of cells are aequos and contains polar charges the polar caps face the internal and external cell while sandwiching the hydrophobic carbohydrate chains in between. For this reason hydrophobic molecules can penetrate through the blood into the brain. This is the reason why, for example heroin, gets you high. This molecule is hydrophobic, allowing an easy pass to the brain. The easier a substance passes to the brain, the faster it has a reaction, and is more likely to produce a high. In this context it is important to note that a substance, like cocain (codein) and ritalin (metalphenedote) act on very similar sides of the brain, yet they have slightly different hydrophobic and/or hydrophilic properties. Ritalin is a little more hydrophilic, causing it to go into the brain slower than cocain and thus not generating a high like cocain. However, there are cases where ritalin is injected directly into the bloodstream to get a high, abusing the substance. A similar

story can be made for codein and heroin. Codein is more hydrophilic than heroin and thereby doesnt enter the brain as fast. That is why codein is commonly prescribed as a cough medicine and doesnt produce highs, whereas heroin does enter fast and is therefor a highly addicting drug. Interestingly, people in the 30s didnt know about all this and heroin was a widely used and prescribed cough medicine. To create commonly used drugs Biochemists make substances more hydrophobic or hydrophilic by binding polar molecules to the carbohydrates. Thus making substances either more or less soluble in the brain by avoiding polar molecules. For example if you want an antibiotic that can fight brain bacteria you want to make it more hydrophobic whereas if you want an antibiotic that is for the stomach you make it hydrophilic. In the case of chemotherapy, a therapy used for the brain, substances are made more hydrophobic. However, in some diseases the brain blood vessels become leaky and thereby let too much water into the brain in addition to poisoning the brain molecules and effecting brain function. This causes symptoms such as nausea, confusion, and in the worst case coma. Another problem occurs when brain tumor cells make their own leaky blood vessels because the tumor wants sugar to enhance its growth; which is one of the problems that make brain tumors so dangerous. However, I only talked about the hydrophobic substances that go into the brain, but how do hydrophilic substances enter the brain? For example, our brain constantly needs glucose, a hydrophilic substance. For this reason the cells in the brain have glucose transporters that transport the glucose into the cell from the blood. These transporters are extremely specific and, for example, the glucose transporter transports only glucose into the brain and nothing else. In addition there are other transporters for other molecules. For example, glutamate transporters or GABA transporters; both are very important neurotransmitters that fulfill very important and very specific regulatory functions. GABA causes inhibition in the brain and glutamate excitation. In the case of any neurological disorders such as epilepsy the flow of these molecules across the membrane is effected. Another good example is the precursor, (which is a molecule that is needed to produce a transmitter) of dopamine, which is

called L-DOPA. L-DOPA is transported through the blood and is recognized by a very specific transporter that transports L-DOPA into the brain and produces dopamine. Dopamine is a very important neurotransmitter, which when dis-regulated or out of balance causes neurological disorders. Dopamine for example is disturbed in ADHD and causes hyperactivity and Attention Deficit. Cocain and Ritalin act on a dopamine transporter. And thereby help save patients that suffer from ADHD. However due to drug abuse it can become very addictive for people without ADHD. Too much dopamine in the brain can lead to schizophrenia; which is why people with a drug history become psychotic which can last for the rest of their life. On the other hand, too little dopamine leads to tremor and rigidity in addition to the inability to initiate a movement or act. Which happens in Parkinson's disease. In the case of Parkinson's a set of nerve cells that produce dopamine are dying. These cells sit in the substantia negra. The only way to restore functions in these patients is to increase the concentration of dopamine in the brain. The problem, however, is that dopamine is polar and charged, and the brain lacks a dopamine transporter. Which means that you can give a patient as much dopamine as you want and it wont affect the brain.

These are the subjects I still need to discuss, however, they are all connected so it shouldnt be too much more. Area Postrema Vomiting center Median Eminents Also, as I said before I haven't worked on this since I started it so it's not very well written; I especially have a problem with comma splices and run on sentences! Sorry! Thank you so much for all your help and understanding!