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Vampires beware

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(NC&T/TSRI) Now, a group of scientists from The Scripps Research Institute, the Genomics Institute of the Novartis Research Foundation, and the Korea University College of Medicine is explaining the biological basis of raw garlic's burn.

In the latest issue of the journal Current Biology, the scientists, led by Scripps Research Associate Professor Ardem Patapoutian and Lindsey Macpherson, who is a graduate student in the Kellogg School of Science and Technology at Scripps Research, describe the cellular and molecular basis of raw garlic's pungency. Raw garlic contains a chemical called allicin that gives it its kick, because the allicin in raw garlic activates a pair of ion channel proteins called TRPV1 and TRPA1 that are expressed on pain-sensing neurons in the mouth.

Garlic ranks second only to salt, perhaps, in terms of flavoring humans have added to food throughout history. The plant originated in the wilds of Central Asia, and it appears in ancient writings by the Egyptian, Babylonian, Indian, and Chinese cultures as far back as 5,000 years ago. The ancient Greeks and Romans were aware of it, and garlic is referred to in writings by Homer, Aristophanes, and Virgil.

Garlic was introduced into Europe by crusaders towards the end of the Middle Ages, migrated to the United States centuries later, and today is a major U.S. crop. According to the Food and Agriculture Organization of the United Nations, the United States produced nearly 300,000 metric tons of garlic in 2004 -- much of that coming from the farmlands of California.

Through the centuries, the plant has enjoyed speculation about its medicinal properties. In Larousse's Gastronomique -- a venerable encyclopedia of food and cooking -- Pliny suggested garlic is a cure for tuberculosis. Hippocrates touted garlic as a laxative. Mohammed maintained garlic as a salve for scorpion stings. Claims are no less bold today, and a simple web search for the health benefits of garlic will turn up page after page touting garlic as a remedy for everything from the common cold to cancer.

Perhaps one reason these beliefs have lingered through the years is that its pungency suggests some sort of potency.

"When you think of garlic," says Patapoutian, "the first thing you think of is the odor."

The plant itself has an unusual number of complex sulfur-containing compounds that give rise to this distinguishing trait. Patapoutian speculates that the unusual combination of chemicals that give rise to garlic's smell evolved as a way to protect the bulbs. Garlic, after all, grows in sandy soil in arid climates, and its bulbs remain close to the surface and easily accessed by all manner of insect, bird, and rodent. Indeed, many species, such as European starlings, ticks, mosquitoes, and worms, are repelled by it.

Humans are sometimes repelled by garlic as well. Writers as far back as Cervantes and Shakespeare warned of garlic's effect on the breath. But paradoxically, the pungency of raw garlic seems to be exactly what appeals to many people -- upscale modern garlic restaurants in San Francisco and Los Angeles have even embraced "stinky" as a proud part of their name.

But there is more to the pungency of raw garlic than just smell. As any cook can tell you, the flavor of raw garlic is markedly different than the flavor of roasted garlic, which is no surprise, really. Roasting garlic, like roasting any vegetable, causes the sugars to caramelize, slightly changing the flavor. But something else changes in the garlic when it is roasted -- its chemical makeup.

Raw garlic is full of sulfurous compounds, including a chemical called alliin, which is concentrated within the body of the garlic, making up about 0.25 percent of the mass of any given clove. When the garlic clove is bruised, chopped, or crushed, the alliin is quickly converted to a chemical known as allicin, a chemical relative of which is present in raw onions. Allicin is itself degraded when garlic is cooked or bruised -- converted by enzymes into other sulfur molecules.

Patapoutian, Macpherson, and their colleagues are now showing that this chemical difference between raw and cooked garlic -- the loss of allicin when garlic is cookedcan account for the change in pungency.

Our experience of raw garlic's pungency is determined by long, specialized neurons embedded in the skin, including the mouth and tongue that the human body uses to detect temperature and pain. Raw garlic activates a class of temperature-detecting molecules known as the transient receptor potential (TRP) ion channels on the surface of these neurons.

TRP channels are something like molecular thermometers. Different TRP channels are generally activated within different temperature ranges, and the integration of these signals is the basis of our ability to sense temperature through the skin. When a person's hand touches ice, for instance, the cold channels on the nerve endings embedded in our skin open up, allowing an influx of positively charged calcium ions into the nerve cell. This influx causes a slight change in the electrical potential of the cell, and when enough channels are activated, the electrical signal causes the neuron to fire.

This neuronal signal travels to the spinal cord and from there to particular brain regions, where it is integrated with others and interpreted as cold.

But TRP channels also detect spicy foods as well. Various TRP channels will be activated by chemicals like capsaicin and cinnamaldehyde, the respective active ingredients in chili peppers and cinnamon sticks, and then they will communicate this information to the brain through the spinal column.

Suspecting that a similar mechanism could account for the pungency of garlic, Patapoutian, Macpherson, and their colleagues studied the effect of raw and cooked garlic and garlic-derived compounds like allicin on pain-sensing neurons and TRP channels. They found raw garlic specifically activates the TRP channels TRPA1 and TRPV1, which are present in the mouth and tongue.

Imagine that you snap off an individual garlic clove from the bunch and peel away the paper-like wrappings. The scent is already strong. Then you pop the clove into your mouth and bite down hard. As you chew the raw garlic, chemicals are released all over your mouth, and when nerve endings in your mouth decorated with TRPA1 and TRPV1 are exposed to the chemicals, the channels open, allow calcium ions outside the cell to rush in, and send a signal to your brain, which processes the information.

"The pungency of garlic is sensed by these two channels," says Macpherson. "Roasted garlic cannot activate these channels in our system."

In their experiments, Macpherson, Patapoutian, and their colleagues tested raw and baked garlic and various compounds found in garlic, and they showed that raw, but not cooked, garlic activates TRPA1 and TRPV1.

Moreover, Macpherson and Patapoutian discovered that allicin is the chemical responsible for garlic's pungency. Allicin activates TRPA1 and TRPV1 more effectively than the compounds derived from it, and the concentration of allicin in raw garlic activates TRPA1 and TRPV1.

Intriguingly, TRPA1 and TRPV1 are both more than just receptors that communicate hot and cold temperatures or the pungency of garlic to the brain. These receptors also communicate pain, and the fact that garlic activates pain receptors is a curious thing. Why should so many humans enjoy raw garlic when the plant has chemicals that cause pain sensations? Garlic seems like something that humans would avoid, just as many other animals do.

This research is also interesting because it is related to Patapoutian's longstanding research into the underlying mechanisms of how we feel pain. Knowing that allicin activates TRPV1 and TRPA1 reveals important information about these receptors, which may help in the eventual design of compounds to modulate the activity of these channels. Indeed, several compounds that block TRPV1's action are currently under investigation for chronic pain indications, and TRPA1 may also be a target for pain therapeutics in the future.

This does not mean, necessarily, that topical garlic would itself be a good candidate for relieving pain -- which is itself a relief for those of us blessed with more acute senses of smell.

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