May 2001

From Massachusetts General Hospital

Study points to potential role for caffeine in reducing the risk of Parkinsonís disease

Coffee drinkers who worry that their morning fix might not be the healthiest of habits may find comfort in a recent report. Working with a mouse model of Parkinson's disease, scientists at Massachusetts General Hospital (MGH) have shown that caffeine is able to prevent the loss of the chemical signal that is depleted in Parkinsonís disease. Published in the May 15th Journal of Neuroscience, the study links caffeine's effects to the A2A receptor located on neural cells next to those that degenerate in Parkinson's patients.

A2A receptors, which bind the molecule adenosine, are found in distinct areas of the brain, and their expression is restricted to the very cells that are targets of the dopaminergic neurons that go awry in Parkinson's disease. "The A2A receptor has a distinct advantage when it comes to treatment because it exists for the most part where you want to target your therapy. So there may be fewer side effects," says Michael A. Schwarzschild, MD, PhD, assistant professor of Neurology at MGH and principal investigator.

Caffeine acts as an antagonist to the A2A receptor, blocking its binding site and rendering it inactive. The scientists found that the effects of caffeine were mimicked by several known A2A antagonists as well as by genetic inactivation of the A2A receptor. The mouse study adds to epidemiological data published last year that documented how much coffee people drank and compared it to whether they developed Parkinsonís. According to Schwarzschild, the results indicate that caffeine may be linked to a decreased risk of Parkinsonís.

"Once this association was found, people asked if caffeine had an effect on the disease, or rather, does Parkinsonís have an effect on caffeine consumption," says Jiang-Fan Chen, MD, PhD, assistant professor of Neurology at MGH and scientific co-director of the project. In other words, perhaps a brain destined to be affected by Parkinsonís also is resistant to caffeine addiction. The current study does not support this theory, though, as it shows that caffeine can prevent the biochemical hallmark of Parkinsonís in the mouse model. "The animal results lend more weight to caffeineís neuroprotective nature," says Schwarzschild. "But the results donít prove it, and they do not provide a rationale for changing caffeine consumption habits." Time will tell if the mouse data will translate to humans, he says.

For their studies, Schwarzschild and his team used a mouse model that mimics the features of Parkinson's diseaseónamely, neural degeneration in the brain associated with a depletion of the neurotransmitter dopamine. Mice exposed to a chemical called MPTP can develop Parkinson's-like symptoms because MPTP causes a decrease in brain dopamine. When the researchers pretreated the mice with caffeine (at levels that would equal about a cup or two of coffee to humans), their brain dopamine levels remained near normal, and thus the MPTP toxicity was decreased.

Interestingly, caffeine's neuroprotective effect may be closely linked to its stimulatory effect. Genetically altered mice that lack A2A receptors experience none of the motor stimulation for which caffeine is so well known.

Dopamine replacement is the standard treatment for Parkinson's disease today. Despite this treatment, the disease continues to progress, often accompanied by motor side effects of the therapy. A2A receptor antagonists can enhance motor function and perhaps even slow disease progression without these complications. "If caffeine is protective through the A2A receptor, more discrete targeting of this receptor may be a good therapy," says Schwarzschild. A2A receptor antagonists are now entering human trials for the treatment of Parkinson's disease. "I look forward to seeing if this basic science lead will be relevant to clinical care," says Schwarzschild.

A complementary paper by Harvard researchers that looks at extensive epidemiological data on caffeine consumption and Parkinson's disease will also be published this month in the Annals of Neurology. The study found that men who regularly drank coffee had a significantly decreased risk of developing Parkinson' s disease. For women, there was a U-shaped correlation, with the lowest risk of developing the disease among women who consumed moderate amounts of coffee (one to three cups a day). Alberto Ascherio, MD, DrPH, of the Harvard School of Public Health, and Walter C. Willett, MD, DrPH, of Brigham and Womenís Hospital, pioneered the work. Schwarzschild together with Chen is collaborating with these researchers and says: "We now have close discussions to see how epidemiological studies can inform our laboratory studies and vice versa. This interdisciplinary approach is very exciting."

Schwarzschild says he hopes that looking at Parkinsonís from different angles may shed light on the development of the disease and offer insight concerning treatment and prevention.

The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Womenís Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.











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