The Promise of Purines: Gardner Center Part of National, Micheal J. Fox-Funded Research Effort

Doctors pose for pictures

Parkinson’s disease specialists and researchers, from left: Fredy J. Revilla, MD (Gardner Center), Michael Schwarzschild, MD, PhD (MassGeneral) and Alberto Espay, MD (Gardner Center). Photo by Cindy Starr/Mayfield Clinic.

Physicians and scientists packed a UC lecture hall last Wednesday to hear Harvard University’s Michael Schwarzschild, MD, PhD, one of the nation’s leading Parkinson’s disease researchers, talk about what’s new in the area of purines, chemical compounds that are being studied at multiple sites – including UCGNI’s Gardner Center — with the help of the largest single investment ever made by the Michael J. Fox Foundation.

Dr. Schwarzschild, an Associate Professor of Neurology who has directed the Molecular Neurobiology Laboratory at the MassGeneral Institute for Neurodegenerative Disease since 1996, discussed two purines — caffeine and urate – which epidemiological studies have shown are associated with reduced risk of developing Parkinson’s and which could lead to new neuroprotective therapies.

Doctors have long observed that coffee drinkers have a much lower risk of getting Parkinson’s, and that people who have Parkinson’s are not typically coffee drinkers. The caffeine purine may work, Dr. Schwarzschild and his team discovered, by blocking adenosine receptors. More precisely, in mouse models of the disease it prevents a signaling molecule called adenosine from docking with one of its receptors (the A2A subtype) on brain cells, thereby disrupting a cell death circuit and promoting cell survivorship.

Although clinical trial results suggest that blockers, or antagonists, of adenosine A2A receptors like caffeine reduce symptoms of Parkinson’s, it is not known whether these A2A antagonists are neuroprotective, that they keep brain cells from dying. “I don’t necessarily recommend that patients drink more coffee,” Dr. Schwarzschild noted. “Laboratory studies show that the blockers may not only help with the symptoms but may also have the additional benefit of slowing down the disease. But it’s not proven.”

The more exciting purine is urate (also known as uric acid), the end product of adenosine metabolism. Primates evolved to have higher levels of urate, an antioxidant that exists in people to greater and lesser degrees.

Recent studies by Dr. Schwarzschild and his colleagues of people recently diagnosed with Parkinson’s showed that people who had higher levels of urate experienced a significantly reduced rate of decline over a period of two years. Those studies established urate as the first molecular marker for the progression of typical Parkinson’s disease.

“It was an unprecedented clue as to why disease progression in Parkinson’s disease is mild in some and aggressive in others,” said Alberto Espay, MD, Assistant Professor of Neurology and a specialist at the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders. “The purine antioxidant urate can serve as a predictor of not only the risk of PD, but also the rate at which it progresses.”

Meanwhile, parallel research in animal models conducted at the Gardner Center has shown that urate levels in the brain can be increased with the administration of inosine, a metabolized form of adenosine that is already present in the body.

Armed with a $5.6 million grant from the Michael J. Fox Foundation, Dr. Schwarzschild and researchers at 17 sites – including the Gardner Center – have begun a randomized, phase II clinical trial in which they are studying the safety of elevating levels of urate through inosine therapy. Because high urate levels can cause some rare but unpleasant side effects, namely gout and kidney stones, the researchers are not enrolling patients who have a history of gout or kidney stones or who already have high levels of urate. In addition, several safety measures have been put in place to minimize these risks for all study participants. Only newly diagnosed patients with low urate levels are being enrolled in the research study, which is known as SURE-PD (Safety of Urate Elevation in Parkinson’s Disease).

“Inosine is part of our metabolism and is widely available as a supplement,” said Dr. Schwarzschild, the study’s principal investigator. “We’re just boosting the levels of it. We are aiming to as much as double the levels of urate in the study participants’ bodies.”

Whether a therapy can reduce symptoms of a disease can be known in a matter of minutes or hours. But a therapy’s ability to slow the progression of an inexorable foe like Parkinson’s can’t be known for some time. The current Phase II SURE-PD research study will be followed by a more expansive, Phase III study. Thus, the question of whether urate can slow the progression of Parkinson’s may take years to answer. Nevertheless, the evidence backing up these research efforts is robust and promising, and clinical researchers like Drs. Schwarzschild and Espay are clearly hopeful and eager to see the results unfold.

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The SURE-PD study is seeking to enroll patients recently diagnosed with Parkinson’s disease who have not yet received any treatment for their disease. Anyone seeking additional information may contact Laura Gaines, the SURE-PD study coordinator, at laura.gaines@uc.edu or (513) 558-1907.

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