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Researchers discover how compounds found in wine thwart disease in mice

UCLA, November/December 2008, by Mark Wheeler — Scientists call it the “French paradox” — a society that, despite consuming food high in cholesterol and saturated fats, has long had low death rates from heart disease. Research has suggested it is the red wine consumed with all that fatty food that may be beneficial — and not only for cardiovascular health but in warding off certain tumors and even Alzheimer’s disease.

Now, Alzheimer’s researchers at UCLA, in collaboration with Mt. Sinai School of Medicine in New York, have discovered how red wine may reduce the incidence of the disease. Reporting in the Nov. 21 issue of the Journal of Biological Chemistry, David Teplow, a UCLA professor of neurology, and colleagues show how naturally occurring compounds in red wine called polyphenols block the formation of proteins that build the toxic plaques thought to destroy brain cells, and further, how they reduce the toxicity of existing plaques, thus reducing cognitive deterioration.

Polyphenols comprise a chemical class with more than 8,000 members, many of which are found in high concentrations in wine, tea, nuts, berries, cocoa and various plants. Past research has suggested that such polyphenols may inhibit or prevent the buildup of toxic fibers composed primarily of two proteins — Aß40 and Aß42 — that deposit in the brain and form the plaques which have long been associated with Alzheimer’s. Until now, however, no one understood the mechanics of how polyphenols worked.

Teplow’s lab has been studying how amyloid beta (Aß) is involved in causing Alzheimer’s. In this work, researchers monitored how Aß40 and Aß42 proteins folded up and stuck to each other to produce aggregates that killed nerve cells in mice. They then treated the proteins with a polyphenol compound extracted from grape seeds. They discovered that polyphenols carried a one-two punch: They blocked the formation of the toxic aggregates of Aß and also decreased toxicity when they were combined with Aß before it was added to brain cells.

“What we found is pretty straightforward,” Teplow said. “If the Aß proteins can’t assemble, toxic aggregates can’t form, and thus there is no toxicity. Our work in the laboratory, and Mt. Sinai’s Dr. Giulio Pasinetti’s work in mice, suggest that administration of the compound to Alzheimer’s patients might block the development of these toxic aggregates, prevent disease development and also ameliorate existing disease.”

Human clinical trials are next.

“No disease-modifying treatments of Alzheimer’s now exist, and initial clinical trials of a number of different candidate drugs have been disappointing,” Teplow said. “So we believe that this is an important next step.”

This work was supported by the National Institutes of Health; the Department of Veterans Affairs; the James J. Peters Veterans Affairs Medical Center Geriatric Research Education Clinical Center Program, Polyphenolics (to Giulio Pasinetti); grants from the Japan Human Science Foundation and the Mochida Memorial Foundation for Medical and Pharmaceutical Research; grants from the Alzheimer’s Association; and the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarkers at UCLA (to David Teplow). Teplow reports no conflict of interests.

The UCLA Department of Neurology encompasses more than a dozen research, clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks first among its peers nationwide in National Institutes of Health funding. For more information, visit http://neurology.medsch.ucla.edu.

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Definition of Polyphenol

Polyphenol: A kind of chemical that (at least in theory) may protect against some common health problems and possibly certain effects of aging.

Polyphenols act as antioxidants. They protect cells and body chemicals against damage caused by free radicals, reactive atoms that contribute to tissue damage in the body. For example, when low-density lipoprotein (LDL) cholesterol is oxidized, it can become glued to arteries and cause coronary heart disease.

Polyphenols can also block the action of enzymes that cancers need for growth and they can deactivate substances that promote the growth of cancers. The polyphenol most strongly associated with cancer prevention is epigallocatechin-3-gallate, or EGCG.

All tea contains polyphenols. Teas and polyphenols isolated from tea have been shown in the laboratory to act as scavengers of oxygen and nitrogen-free radicals, protecting the fatty membranes of cells, proteins and DNA. However, the results of human studies of tea and polyphenols to date (2001) have been inconsistent and have yet to prove anything one way or the other as regards the value of polyphenols.

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Credit: Reid Parham

Use of drugs to enhance memory and concentration should be permitted, experts say.

MIT Technology Review, December 8, 2008, by Emily Singer — Off-label use of stimulants, such as Ritalin, is on the rise among college students. Studies show that 5 percent to 15 percent of students use prescription drugs as study aids, and surveys suggest the practice may be common among academics as well. The trend has sparked debates over how and when these cognitive enhancers should be used. Military personnel routinely use stimulants while on active duty, but should that practice also be permitted among surgeons working long shifts? What about scientists working late nights in the lab? Or students taking exams?

A commentary appearing today online in the journal, Nature, advocates for broad access to brain-boosting drugs. According to the piece, written by a group of ethicists, psychologists, and cognitive neuroscientists, “cognitive enhancement, unlike enhancement for sports competitions, could lead to substantive improvements in the world.” While opponents have argued that the use of performance-enhancing drugs is unfair and could undermine the value of hard work, the authors say that these drugs fall into the same category as more common efforts to increase brain function, such as drinking a cup of coffee, or getting a good night’s sleep, and thus should be regulated accordingly.

One of the biggest concerns associated with broad access to these drugs is that people will feel pressured to take them to get ahead, or just to keep up. An informal survey conducted by Nature last year of 1,400 people from 60 countries found that 20 percent of respondents engaged in off-label use of drugs to enhance concentration and memory. Ritalin was the most popular, followed by Adderall. Both are prescribed for ADHD. The survey confirmed the potential for peer pressure; while 85 percent of respondents said that the use of these drugs by children under the age of 16 should be restricted, a third said they would feel pressure to give them to their children if others were using them.

The authors of the commentary also note that if cognitive enhancers are to be used more broadly, more extensive study of the risks and benefits of the drugs is sorely needed. The side effects of long-term stimulant use, especially in children, are not yet known. And the potential for dependence and abuse has not been well documented.

Michael Gazzaniga, director of the Sage Center for the Study of Mind at the University of California, Santa Barbara and one of the authors of the commentary, talked with Technology Review about the potential benefits and drawbacks of these drugs.

MIT Technology Review: The commentary suggests that healthy adults should have access to cognitive-enhancing drugs. Why do you think this is a good idea?

Gazzaniga: Normal ageing finds one’s memorial processes not what they use to be. If there were drugs that helped and were safe, I would certainly be for them being available to the public.

TR: The commentary argues that cognitive-enhancing drugs “should be viewed in the same general category as education, good health habits, and information technology.” Why do you think this is true?

MG: All new technologies are at first resisted, even the typewriter. When changing mental states, people get antsy, especially when it appears to enhance capacity. There is somehow a sense one is cheating the system. Well, so is chemotherapy. When all of these new technologies are used in moderation and the right social context, they are a good.

TR: Do you think it’s possible to avoid making people feeling obligated to take these drugs to keep up? Especially given the huge amount of money spent on pharmaceutical advertising and the broad impact it has been shown to have?

MG: Rates of off-label drug use will stabilize. I think they will stay low. One could easily obtain Ritalin now for afternoon lassitude but the vast majority of people don’t. The afternoon cup of tea or coffee sustains and seems to do the trick for most of us.

TR: Really? What about in high-pressure situations, like academia?

MG: Remember, these drugs don’t make you smarter. They keep you awake so you can study so you can be smarter. While there are always fads of use with such products, usage will settle down to a base rate. That base rate may be higher than some people like, but it will be established no matter what the external drug policy might be.

TR: What about the potential for abuse and dependence? How would you ensure they are used responsibly?

MG: Education is the only tool that works. As we have learned from illicit drug use, it is virtually impossible to keep drugs out of a community. The rate of demand for any given drug, whether illicit or off-label legal, is set by the local social context. One can’t ensure drug products will always be used responsibly. It is up to each community to teach about the hazards of inappropriate drug use and, by doing so, control the base rate of use. It is not a perfect world!

TR: One of the major arguments against widespread use of cognitive-enhancing drugs is that it’s “the easy way out.” Why do you disagree?

MG: Most of these drugs are used in spurts when huge mental demands are called for. They are not for everyday mental routines. Having said that, I think it is a fair concern to make sure people don’t become dependent on them as a way of life. Working above one’s pay grade in the end has tremendous costs.

TR: What are some of the safety concerns? When giving drugs to healthy people, tolerance for risk is low.

MG: As it should be. Remember, do no harm. I think the concerns are on the mental states if misused. Images might be too vivid, for example. Careful tests and analysis should be run.

TR: Why do you think the idea of using drugs to enhance cognitive function makes people so uncomfortable?

MG: Messing around with the mind is a dangerous and delicate matter. None of this should be taken lightly.

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Flowing liquid: In this three-dimensional device, dyes move through four channels in a basket-weave pattern. By using several alternating layers of treated paper and perforated waterproof tape, the researchers are able to direct liquids to different testing areas.
Credit: Andres Martinez

By adding tape, researchers can make more-complex tests.

MIT Technology Review, December 8, 2009, by Kristina Grifantini — On the desk of Harvard University professor George Whitesides are white sheets the size of stamps. Each is inlaid with a different pattern: a four-leaf flower, concentric circles surrounding four dots, a six-pointed burst. These prototypes are diagnostic tests made from a cheap, universally available substrate: paper. With the simple addition of tape, Whitesides and his group have been able to turn their paper tests into three-dimensional devices, allowing for more-complicated analysis. Such paper “lab on a chip” tests may lead to a cost-effective, portable, and accurate method for diagnosing diseases in countries lacking reliable health care.

Whitesides holds up his group’s latest development: a square slightly thicker than the other samples, covered in a grid of yellow, greed, red, and blue dots. This prototype is made up of layers of patterned paper, between which are waterproof double-sided tape. By layering the squares and connecting them with tape adhesive, the group is able to channel liquid horizontally and vertically in a very small area, as detailed in this week’s Proceedings of the National Academy of Sciences.

Each square of paper–which naturally soaks up liquid in its fibers–has been treated with photoresist material, to create channels that funnel liquid to tiny wells coated with proteins or antibodies. The fluid interacts with that area of the paper and turns the well a certain color, changing hues, for example, with varying concentrations of glucose.

“You can effectively make three-dimensional systems,” says Whitesides. “You can distribute fluid from a single point of origin to multiple points elsewhere.” Most microfluidic systems, he adds, require sophisticated piping to channel the fluid, but just by drawing water-resistant channels in the paper and using waterproof tape, the researchers have been able to control the movement of the liquid.

A sample of biological fluid is pressed onto one side of the paper chip. Photoresist channels guide the fluid to certain wells and ultimately through a tiny hole in the waterproof tape, which funnels the liquid on to the next piece of paper. This process continues for each layer of the chip, and the results appear in a dotted grid on the final layer.

According to Whitesides, “Each dot would be a different test” that could be performed using a single drop of blood serum. Currently, the researchers layer the paper and tape by hand, which Whitesides says is fairly easy to do, but they hope that eventually a device could be made to print the tape and paper.

The group has focused on readily accessible materials, so the device can be robust and used in a variety of environments and in developing countries. They chose paper because its natural capillary action circumvents the need for expensive or cumbersome pumps and power sources to move the liquid (as would be needed for polymer or glass microfluidic devices). In that way, the device is similar to how pH paper or a pregnancy test works. But Whitesides aims for his tests to diagnose much more, as well as be portable, cheap to manufacture, and easy for those in developing countries or in military or emergency respond teams to use and adapt.

“These paper-based devices may allow significantly cheaper and portable analytical devices for diagnostics in the developing countries,” says Mehmet Fatih Yanik, an assistant professor of electrical engineering at MIT, who works on lab-on-a-chip imaging. “They could also allow routine conduction of hundreds of assays cheaply, which may allow early and precise diagnostics of severe diseases, significantly reducing the health-care burden,” he adds.

Although the tests are still in the research and development phase, Whitesides says, so far, they seem to be highly accurate. Whitesides has already cofounded a nonprofit, Diagnostics for All, to further develop and distribute the tests in a developing country. (Diagnostics for All won the MIT $100K Entrepreneurship Competition earlier this year.)

The researchers have also begun work on coupling the paper tests with cell phones, so that the results can be photographed, sent to a center, and read by a technician who can send recommendations back via phone.

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Gary Wenk

Ohio State University, December 8, 2008 – The more research they do, the more evidence Ohio State University scientists find that specific elements of marijuana can be good for the aging brain by reducing inflammation there and possibly even stimulating the formation of new brain cells. The National Institutes of Health supported this research.

The research suggests that the development of a legal drug that contains certain properties similar to those in marijuana might help prevent or delay the onset of Alzheimer’s disease. Though the exact cause of Alzheimer’s remains unknown, chronic inflammation in the brain is believed to contribute to memory impairment.

Any new drug’s properties would resemble those of tetrahydrocannabinol, or THC, the main psychoactive substance in the cannabis plant, but would not share its high-producing effects. THC joins nicotine, alcohol and caffeine as agents that, in moderation, have shown some protection against inflammation in the brain that might translate to better memory late in life.

“It’s not that everything immoral is good for the brain. It’s just that there are some substances that millions of people for thousands of years have used in billions of doses, and we’re noticing there’s a little signal above all the noise,” said Gary Wenk, professor of psychology at Ohio State and principal investigator on the research.

Wenk’s work has already shown that a THC-like synthetic drug can improve memory in animals. Now his team is trying to find out exactly how it works in the brain.

The most recent research on rats indicates that at least three receptors in the brain are activated by the synthetic drug, which is similar to marijuana. These receptors are proteins within the brain’s endocannabinoid system, which is involved in memory as well as physiological processes associated with appetite, mood and pain response.

This research is also showing that receptors in this system can influence brain inflammation and the production of new neurons, or brain cells.

“When we’re young, we reproduce neurons and our memory works fine. When we age, the process slows down, so we have a decrease in new cell formation in normal aging. You need those cells to come back and help form new memories, and we found that this THC-like agent can influence creation of those cells,” said Yannick Marchalant, a study coauthor and research assistant professor of psychology at Ohio State.

Marchalant described the research in a poster presentation Wednesday (11/19) at the Society for Neuroscience meeting in Washington, D.C.

Knowing exactly how any of these compounds work in the brain can make it easier for drug designers to target specific systems with agents that will offer the most effective anti-aging benefits, said Wenk, who is also a professor of neuroscience and molecular virology, immunology and medical genetics.

“Could people smoke marijuana to prevent Alzheimer’s disease if the disease is in their family? We’re not saying that, but it might actually work. What we are saying is it appears that a safe, legal substance that mimics those important properties of marijuana can work on receptors in the brain to prevent memory impairments in aging. So that’s really hopeful,” Wenk said.

One thing is clear from the studies: Once memory impairment is evident, the treatment is not effective. Reducing inflammation and preserving or generating neurons must occur before the memory loss is obvious, Wenk said.

Marchalant led a study on old rats using the synthetic drug, called WIN-55212-2 (WIN), which is not used in humans because of its high potency to induce psychoactive effects.

The researchers used a pump under the skin to give the rats a constant dose of WIN for three weeks – a dose low enough to induce no psychoactive effects on the animals. A control group of rats received no intervention. In follow-up memory tests, in which rats were placed in a small swimming pool to determine how well they use visual cues to find a platform hidden under the surface of the water, the treated rats did better than the control rats in learning and remembering how to find the hidden platform.

“Old rats are not very good at that task. They can learn, but it takes them more time to find the platform. When we gave them the drug, it made them a little better at that task,” Marchalant said.

In some rats, Marchalant combined the WIN with compounds that are known to block specific receptors, which then offers hints at which receptors WIN is activating. The results indicated the WIN lowered the rats’ brain inflammation in the hippocampus by acting on what is called the TRPV1 receptor. The hippocampus is responsible for short-term memory.

With the same intervention technique, the researchers also determined that WIN acts on receptors known as CB1 and CB2, leading to the generation of new brain cells – a process known as neurogenesis. Those results led the scientists to speculate that the combination of lowered inflammation and neurogenesis is the reason the rats’ memory improved after treatment with WIN.

The researchers are continuing to study the endocannabinoid system’s role in regulating inflammation and neuron development. They are trying to zero in on the receptors that must be activated to produce the most benefits from any newly developed drug.

What they already know is THC alone isn’t the answer.

“The end goal is not to recommend the use of THC in humans to reduce Alzheimer’s,” Marchalant said. “We need to find exactly which receptors are most crucial, and ideally lead to the development of drugs that specifically activate those receptors. We hope a compound can be found that can target both inflammation and neurogenesis, which would be the most efficient way to produce the best effects.”

The National Institutes of Health supported this work.

Coauthors on the presentation are Holly Brothers and Lauren Burgess, both of Ohio State’s Department of Psychology.