ARTICLE IN BRIEF
SEVERAL BASIC SCIENCE papers have found that ibuprofen was neuroprotective for Parkinson disease.
I buprofen, alone among nonsteroidal anti-inflammatory drugs (NSAIDs), appears to have a neuroprotective effect against Parkinson disease (PD), according to new research published in the March 2 online edition of Neurology.
In a prospective observational study of 136,197 participants in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) who had been free of PD at baseline, scientists at Harvard University and Massachusetts General Hospital found that self-reported regular users of ibuprofen (two-plus times a week) had a significantly lower risk of PD than non-users, with a relative adjusted risk of 0.62 (95% CI: 0.42, 0.93; p=0.02). The same effect was not seen for users of aspirin, acetaminophen, and other NSAIDs. Similar results were seen in a pooled meta-analysis.
Ali Samii, MD, professor of neurology at the University of Washington and clinical director of the Seattle component of the Northwest Parkinson Disease Research Education and Clinical Center at the VA Puget Sound Health Care System Seattle, was not at all surprised by these findings. “In a meta-analysis with Canadian colleagues published in Drugs and Aging in 2009, we found a result that was almost the same,” said Dr. Samii, who was not involved with the current study. “We took all the papers that had data on the use of NSAIDs and the risk of developing Parkinson disease, and the pooled risk ratio with ibuprofen was about 0.76. Based on our research, taking ibuprofen regularly reduced the risk of getting Parkinson disease by about 1 in 4.”
Dr. Samii's meta-analysis also found ibuprofen to be unique among NSAIDs in this regard. “It might be something specific about ibuprofen, such as better penetration across the blood-brain barrier,” he said. “There are also a number of basic science papers, especially in the mouse model of PD, indicating that ibuprofen may be neuroprotective.”
The paper's authors noted that ibuprofen displays protective properties not shared by aspirin and other NSAIDs in inflammatory and oxidative stress models of Parkinson. “Ibuprofen acts as a ligand for PPAR-gamma [peroxisome proliferator-activated receptor-gamma], a novel therapeutic target for PD,” they wrote. “PPAR-gamma can inhibit apoptosis and oxidative damage…In a recent animal study, ibuprofen, but not aspirin, significantly attenuated the reduction of PPAR-gamma expression and dopamine transporter-positive signals, and controlled the accumulation of activated microglial cells induced by methamphetamine.”
While impressed by the study, Demetrius Maraganore, MD, Ruth Cain Ruggles Chairman of the Department of Neurology and medical director of the Neurological Institute at North Shore University Health System in Chicago, remains cautious. “We would love very much to think that ibuprofen reduces the risk for Parkinson disease, because there are 20 people in any population of 100,000 a year who are going to get this disease, and 2 percent of us are going to get it during our lifetime. It's a disease that costs the United States more than $23 billion a year. Anything that we can identify that would reduce that burden to the individual and to society, especially something as simple as taking ibuprofen, would be wonderful,” he said. “But we have to be careful because this is an observational study and therefore there are limitations inherent to this type of research.”
For example, he noted that the paper does not report controlling for exercise levels. “Since exercise has in the past been found to have a neuroprotective effect against Parkinson disease, and since we might assume that people who exercise frequently would also use ibuprofen more frequently for muscle pain and fatigue, this would be an important factor.”
Although the paper itself does not describe controlling for exercise, corresponding author Xiang Gao, MD, PhD, instructor in medicine at Harvard Medical School and associate epidemiologist at Brigham and Women's Hospital, reported that that analysis was done and that results did not change materially after adjusting for the exercise variable.
And even in a cohort as well-documented as the NHS and HPFS, there are limitations. “Health care workers tend to be pretty good at recalling details in their medical history,” Dr. Maraganore acknowledged. “But ironically, I myself saw a new physician yesterday for the first time, and he was asking me some questions about past medical milestones in my history. I couldn't give him an accurate estimate of what year I had this or that done. So even as a physician, I can imagine that my recall of my NSAID use — and at what doses and over what period of time — would be limited.”
Dr. Maraganore also pointed out that physicians may not be the best population in which to study a possible protective agent against PD. “In research I published with colleagues at the Mayo Clinic [a 2006 paper in Neurology], we found that physicians [and others with nine or more years of education] are at higher risk of developing Parkinson disease,” he said. “Since physicians are by definition at greater risk, they are not a representative sample.”
CHALLENGES FOR FUTURE RESEARCH
“I would like to see more studies to confirm our observations,” said Dr. Gao. “If this study is confirmed by future clinical trials among individuals with early-stage PD, ibuprofen could be considered a neuroprotective agent in the disease.”
The challenge, said Dr. Samii, is how to construct such a trial. To date, there have been no randomized clinical trials of any anti-inflammatory agents in active PD. “Once patients are on medication for Parkinson disease, that would make the results harder to follow,” he noted. “Such a trial would probably best be done in the very early stages of the disease, ideally in people who do not yet take symptomatic medications for it, and see if it can actually change their motor progression over a certain time period.”
“Right now, this study shows primary prevention, but not secondary prevention,” agrees Dr. Maraganore. “Based on the information we have to date, I couldn't recommend to patients with Parkinson disease that they should start taking ibuprofen. At minimum, we need an observational study of patients with the disease, measuring cumulative dose exposures to ibuprofen and stratifying them based on whether they used it or not.” •