Multiple Sclerosis Newsletter

Multiple Sclerosis Newsletter
Northern Colorado Edition

October - November 2006

Research Updates

Crossing the Barrier
Grit Vollmer Scientific American Mind, June/July 2006

[Commentary: Ever wonder what the 'blood brain barrier' is? Me too, and this description from Scientific American Mind magazine is so well written that even I could understand it. Some really good information in here - even why your kid should never use Ecstasy - ever! Donita]

Paul Ehrlich had just injected aniline dye--used to color blue jeans'into a rat's bloodstream. For years the immunologist had been working on ways to stain cells so they would be more visible under a microscope, and aniline looked promising. Soon, all the animal's muscles, blood vessels and organs were deep indigo. But for some confounding reason, the central nervous system - the brain and spinal cord - remained untouched.

Ehrlich's experiment, done at Berlin's Charite hospital in 1885, provided early evidence for the blood-brain barrier - a vital wall that controls which molecules in the bloodstream can enter the brain or nerve pathways. Oxygen, sugars and amino acids are allowed in; most compounds are kept out. As a result, the brain can do its job inside a secure perimeter not available to any other organ, which is handy because substances in air, water and food - as well as toxins and even the body's own hormones - can severely impair the brain's functioning. Easy access would quickly lead to mental chaos.

This brilliant defense can be a cursed impediment to curing brain diseases, however. Almost no therapeutic drugs can penetrate the blockade. William Pardridge, professor of medicine at the University of California, Los Angles, says 98 percent of drugs that have some effect on the central nervous system cannot cross into the brain. Pharmaceuticals cannot battle meningitis, rabies, tumors, Alzheimer's or multiple sclerosis, because they cannot reach the sites where the diseases are wreaking havoc. Nevertheless, scientists have greatly improved their understanding of the sophisticated mechanisms the blood-brain barrier uses to grant or deny admission, and they are devising ways to exploit those mechanisms to sneak therapeutic drugs through.

No Trespassing: It can be hard to visualize the blood-brain barrier. It is not a filter at the base of the head or an envelope surrounding the brain and spinal cord. It is a layer of special, tightly knit cells-a carpet-that lines the inner walls of all the small blood vessels that reach into the brain and spinal cord. Like soldiers standing shoulder to shoulder, these endothelial cells allow only certain molecules to pass from the blood on one side of them into the region of nerve cells on the other.

Thomas Reese and Morris Karnovsky, faculty members at Harvard Medical School, first made the blood-brain barrier visible in 1967, using an electron microscope. They discovered endothelial cells tightly packed along the blood vessel walls. Tough proteins tie each endothelial cell to its neighbors, filling the space between them so nothing can squeeze through. (In blood vessels serving other organs, the endolethial cells are loosely connected, so substances can readily slide between them.) The only way that a molecule in the bloodstream can reach the nerve tissue is to pass right through the endothelial cell bodies themselves.

Of course, the brain cannot be completely shut out. Its cells need nutrients to survive and function correctly. Because of their tiny size, molecules such as oxygen can diffuse right through the guard cell bodies. But so can alcohol, nicotine, heroin and the party drug ecstasy. Larger molecules such as glucose are funneled in through selective gates, and others such as iron are cloaked inside special transporters that ooze through the cells.

A few substances, especially ecstasy, actually damage the barrier as they cross it. Bryan Yamamoto, a pharmacology professor at Boston University, gave the party drug to rats, then injected them with a dye that is normally too large to cross the blood-brain barrier. The dye easily reached the brain. The rats received no more ecstasy, yet even 10 weeks later newly injected dye still was able to enter the brain. The ecstasy had made the blood-brain barrier far more permeable for an extended time-exposing the brain to pathogens. Yamamoto cannot say how long the drug's effect lasts in humans, but 10 weeks in a rat's life corresponds to five to seven human years.

Certain viruses and bacteria, such as those causing rabies, meningitis and cholera, trick the blood-brain barrier by attacking the proteins on the endothelial cells, forcing open the gates. Brain tissue may then become dangerously inflamed, but there is at least one positive consequence: the swelling weakens the barrier, making it a bit easier for immune system cells to push through and fight the infection.

In the case of multiple sclerosis, the same mechanism goes out of control. Hordes of immune cells shove their way into the brain, exacerbating the inflammation reaction. Multiple sclerosis is indeed a disease of the blood-brain barrier; only after immune cells are suddenly able to flood across the border do they attack the myelin sheaths around nerves. These sheaths insulate the nerves, enabling them to conduct signals quickly and cleanly; as myelin is destroyed, nerve impulses become erratic and destructive.

Trojan Horses: Many therapeutic drugs that might fight brain diseases are simply too large to diffuse through unnoticed, the way ecstasy and heroin do. Ironically, another defense mechanism thwarts the transport of even small medications past the barrier. So-called export pumps snare 'foreign' molecules as they begin to cross the endothelial cells and expel the invaders back into the bloodstream. Scientists are therefore devising tricks to sneak drugs around the export pumps or temporarily disable them.

Researchers at the University of Veterinary Medicine, in Hannover, Germany, have constructed a blocking molecule that binds to a protein that operates the pumps, preventing the protein from initiating the pumping action. In rats, the inhibitors make the barrier more permeable. Initial tests on epilepsy patients have reduced the number of seizures related to overactivity of the pumps.

A basic problem exists with this general approach, however. Disabling the export pumps in the brain also disables the pumps in linings that protect other organs throughout the body, exposing them to influxes of harmful substances that are normally rejected. Therefore, Gert Fricker, a biochemist at the Institute for Pharmacy and Molecular Biotechnology at the University of Heidelberg in Germany, is trying a different scheme: devising disguises for drugs.

Fricker and his team are crafting tiny, hollow spheres called liposomes that will sneak drugs through the wall like Trojan horses. The spheres are made of lipids-fatty complexes-and slide through the lipid-embracing epithelial cells while holding drug molecules inside their hollow cores. He is also tacking natural antibodies onto the outsides of liposomes that can latch onto receptors in the wall that will, in turn, pull the liposome through. At U.C.L.A., Partridge has had similar successes. Victor Shashoua, formerly a biomedical researcher at Harvard Medical School, has used a fatty acid to sneak in dopamine, a neurotransmitter that is lacking in several brain illnesses, such as Parkinson?s disease.

Doctors already use such Trojan horses-sometimes called drug taxis-to deliver medication to other organs, for example, to fight stomach cancer. For brains, researchers have used this method only on lab animals thus far; clinical human studies are still in the planning stage.

Fricker's team is also working on alkylglycerols with the National Institute of Environmental Health Sciences in Research Triangle Park, N.C. These molecules are soluble in both lipids and water and in limited tests have succeeded in opening the barrier to chemotherapeutic compounds. For reasons that are not fully understood, the alkylglycerols open the vital barrier for just a few minutes so the therapeutic agents can cross. Then the wall seems to close naturally again. The short span of permeability would make it less likely that dangerous molecules could also reach the brain, the way ecstasy is allowed in. Experimenters at U.C.L.A. and at Ohio State University have introduced anticancer compounds into a rat's bloodstream that open up only the part of the barrier that is close to a brain tumor.

These advances and others are giving scientists hope that one day doctors will have a full bag of tricks they can use to exploit the blood-brain barrier. In these cases, the brain won't mind being fooled.

THE BLOOD-BRAIN-BARRIER (BBB) 'Keep Out'
Neuroscience for Kids

Over 100 years ago it was discovered that if blue dye was injected into the bloodstream of an animal, that tissues of the whole body EXCEPT the brain and spinal cord would turn blue. To explain this, scientists thought that a ?Blood-Brain-Barrier (BBB) which prevents materials from the blood from entering the brain existed. More recently, scientists have discovered much more about the structure and function of the BBB.

Anatomy of the BBB:
The BBB is semi-permeable; that is, it allows some materials to cross, but prevents others from crossing. In most parts of the body, the smallest blood vessels, called capillaries, are lined with endothelial ells. Endothelial tissue has small spaces between each individual cell so substances can move readily between the inside and the outside of the vessel. However, in the brain, the endothelial cells fit tightly together and substances cannot pass out of the bloodstream. (Some molecules, such as glucose, are transported out of the blood by special methods.)

Glial cells (astrocytes) form a layer around brain blood vessels and may be important in the development of the BBB. Astrocytes may be also responsible for transporting ions from the brain to the blood.

Functions of the BBB:
The BBB has several important functions:
1. Protects the brain from 'foreign substances' in the blood that may injure the brain.
2. Protects the brain from hormones and neuro-transmitters in the rest of the body.
3. Maintains a constant environment for the brain.

General Properties of the BBB
1. Large molecules do not pass through the BBB easily.
2. Low lipid (fat) soluble molecules do not penetrate into the brain. However, lipid soluble molecules, such as barbiturate drugs, rapidly cross through into the brain.
3. Molecules that have a high electrical charge to them are slowed.

The BBB can be broken down by:
1. Hypertension (high blood pressure): high blood pressure opens the BBB.
2. Development: the BBB is not fully formed at birth.
3. Hyperosmolitity: a high concentration of a substance in the blood can open the BBB.
4. Microwaves: exposure to microwaves can open the BBB.
5. Radiation: exposure to radiation can open the BBB.
6. Infection: exposure to infectious agents can open the BBB.
7. Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the BBB.

Circumventricular Organs:
There are several areas of the brain where the BBB is weak. This allows substances to cross into the brain somewhat freely. These areas are known as 'circumventricular organs'. Through the circumventricular organs the brain is able to monitor the makeup of the blood. The circumventricular organs include:

Pineal body: Secretes melatonin and neuroactive peptides. Associated with circadian rhythms.

Neurohypophysis (posterior pituitary): Releases neurohormones like oxytocin and vasopressin into the blood.

Area postrema ??Vomiting center?: when a toxic substance enters the bloodstream it will get to the area postrema and may cause the animal to throw up. In this way, the animal protects itself by eliminating the toxic substance from its stomach before more harm can be done.

Subfornical organ: Important for the regulation of body fluids.

Vascular organs of the lamina terminalis: A chemosensory area that detest peptides and other molecules.

Median eminence: Regulates anterior pituitary through release of neurohormones.

POSITIVE RESULTS REPORTED FOR ORAL TERIFLUNOMIDE FOR RELAPSING MS
Nat. M.S. Society, May 12, 2006

An experimental oral drug being tested for multiple sclerosis, called teriflunomide (Sanofi-Aventis), significantly reduced MRI-detected disease activity in a 36-week, Phase II clinical trial involving 179 people with relapsing MS. Teriflunomide is an agent that may modulate T cells, which drive the immune attack in MS. Paul O'Connor, MD (University of Toronto) and colleagues originally reported these results at the 2004 Congress of the European Committee for Treatment and Research in MS, and have now published the findings in Neurology (2006 Mar 28:66(6):894-900).

Dr. O'Connor and his team recruited 157 people with relapsing-remitting MS (characterized by clearly defined flare-ups followed by partial or complete recovery periods), and 22 people with secondary-progressive MS (a secondary stage of the disease involving a steadily worsening course, occurring with or without relapses) with relapses. Participants were randomly assigned to receive inactive placebo, or one of two doses (7 mg or 14 mg) of teriflunomide, once daily for 36 weeks. The primary objective of the study was to determine the effect of treatment on the average number of active areas of disease activity (lesions) observed on MRI scans taken every six weeks. Secondary objectives included the frequency of relapses, and any increase in disability as measured by the EDSS, a standard scale.

Both treatment doses were associated with reduced numbers of active lesions compared with placebo. Significantly fewer people in the group taking the higher dose showed an increase in the EDSS than those in the placebo group. The drug was well tolerated; adverse events included headache and upper respiratory tract infection, and were similar among all three groups.

A larger study of teriflunomide is underway in people with relapsing-remitting MS in North America and Europe; more information is available on the ClinicalTrials.gov Web site, at:

http://www/clinicaltrials.gov/ct/show/NCT00134563.

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