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Restricting diet may reverse early-stage Parkinson's disease

November 16, 2005

OHSU/VAMC study shows mice consuming fewer calories experience boost in essential neurochemical

PORTLAND, Ore. - A new Oregon Health & Science University and Portland Veterans Affairs Medical Center study suggests that early-stage Parkinson's disease patients who lower their calorie intake may boost levels of an essential brain chemical lost from the neurodegenerative disorder.

The study by Charles Meshul, Ph.D., associate professor of behavioral neuroscience in the OHSU School of Medicine and the VAMC's Neurocytology Lab, shows that dietary restriction reverses a Parkinson's-induced drop in glutamate, a brain neurotransmitter important for motor control, function and learning, in a mouse model for the disease's early stages.

The results, presented today at the Society for Neuroscience's 35th annual meeting in Washington, D.C., are the first to show that a restricted diet can disable neurochemical changes in the brain occurring in early-stage Parkinson's even after those changes are observed.

"In the early stages of the disease, we see certain markers in the brain that are changing that may be indicative that dietary restriction is helpful," Meshul said.

Parkinson's disease is a progressive, degenerative disorder affecting a region of the brain called the substantia nigra where movement is controlled. Symptoms such as tremor or shaking, muscular stiffness or rigidity, slowness of movement and difficulty with balance appear when about 80 percent of cells in the body that produce the neurochemical dopamine die or become impaired.

Incidence increases with age, and the disease is uncommon in people younger than 40. According to the OHSU Parkinson Center of Oregon, the disease affects both men and women across all ethnic lines and occurs in about two of every 100 people older than 55. About 1.5 million Americans suffer from the disease.

Meshul's lab compared two groups of mice with 60 percent to 75 percent loss of dopamine in the brain, representing early-stage Parkinson's: One had access to food every day while the other had access every other day, and both were fed over a 21-day period. The mice that ate less often lost 10 percent to 15 percent of their body weight compared to their counterparts.

"Dietary restriction appears to be normalizing the levels of glutamate," Meshul said. "The fact that we're getting the levels of glutamate back to, essentially, control levels may indicate there are certain synapse changes going on in the brain to counteract the effects of Parkinson's. In fact, what this may indicate is a reversal of locomotor deficits associated with the disease."

In addition to the rise in glutamate, Meshul's group, using a dopamine-synthesizing enzyme called tyrosine hydroxylase as a marker for dopamine nerve terminals, found that dietary restriction caused a drop in the number of dopamine terminals in the mouse model for early-stage Parkinson's.

"As it turns out, dietary restriction, in and of itself, had an effect. It actually caused a small but significant decrease in the numbers of these dopamine terminals. So in other words, dietary restriction really is doing something to the brain," Meshul said. "It could very well be that what dietary restriction is doing is trying to protect the system somehow. And one of the reasons dietary restriction is protective may be that it's reducing the activity of particular synapses. That's actually what the data indicates."

Matching the upturn in glutamate levels with positive behavioral changes is difficult at this point in the research, Meshul said. "One of the unfortunate problems with this model is it's tough to do any behavioral measures. We see a reversal of the effect of glutamate in the brain due to the dietary restriction, but what does that actually mean in terms of the behavior of the animal? Unfortunately, we don't know. We didn't measure that."

But a similar primate study at the University of Southern California that Meshul is associated with is testing the hypothesis that glutamate does have an effect on behavior. "It turns out that, in time, these animals recover behaviorally from all of the motor deficits that are associated with (early-stage Parkinson's)," he said. "Our hypothesis is there may be changes in glutamate that account for these behavioral changes."

Dietary restriction's beneficial effect on neurological function has been studied in primates by scientists at the National Institutes of Health for 30 years, Meshul said. Researchers found that animals whose calorie intake was lowered by 20 percent aged better, suffered from fewer immunological disorders, displayed healthier hair and skin tone, and "looked significantly better than a counterpart that hasn't had a restricted diet."

"They live longer," Meshul said. "It's been known for many, many years that dietary restriction is good."

Scientists already have shown dietary restriction initiated before the onset of early Parkinson's can protect against neurochemical changes in the brain caused by the disease. In 1999, researchers found that mice on restricted diets for three months prior to an early Parkinson's diagnosis lost fewer dopamine-synthesizing neurons.

"There's not as much loss of dopamine if you restrict their diets ahead of time," Meshul noted.

Meshul's lab is finding that dietary restriction isn't the only way to boost neurological function in Parkinson's disease. Early results of another study the group is conducting have shown that rats with 90 percent loss of dopamine in the brain - or full-blown Parkinson's disease - under a four-week exercise regimen can run twice as long as parkinsonian rats that didn't exercise.

"We're trying to make the correlation that exercise definitely helps in terms of the parkinsonian animal and, in fact, in human studies it's been shown that any sort of exercise helps patients," Meshul said.

Oregon Health & Science University