Mice and rats treated with uric acid, a small naturally occurring molecule, were more likely to survive and have better functional outcomes following a stroke than animals treated with placebo (saline infusion). The findings from a University of Iowa-led research team add to mounting evidence that uric acid protects the brain during stroke and may help to improve outcomes for the almost 795,000 Americans who have a stroke every year.
Stroke is a leading cause of death and long-term disability. Ischemic stroke, caused by a blockage of blood flow to the brain, is the most common type of stroke. Rapid treatment to remove the blockage and restore blood flow and can be lifesaving and lessen the chance of long-term disability for patients. However, the damage caused to brain cells during the initial stroke and reperfusion—the process when blood flow is restored to the brain—can still lead to significant disability.
Previous research by the UI team, led by Enrique Leira, MD, MS, UI professor of neurology, neurosurgery and epidemiology, and Anil Chauhan, PhD, UI professor of internal medicine, and their collaborators, has shown that uric acid may be able to minimize this damage. This “cerebroprotective” effect makes uric acid an attractive candidate to add to current stroke therapy.
“Our data so far suggests that giving an intravenous infusion of uric acid at the time of stroke treatment could help protect brains during stroke and improve long-term outcomes for patients,” Leira says.
The new study, published recently in the journal Stroke, shows that uric acid provides cerebroprotection when tested in both male and female rodents that had health factors common to patients that have a stroke, including older age, obesity, and high blood pressure.
“These results support the candidacy of uric acid as a brain-protecting therapy in stroke treatment and allowed us to pursue a human clinical trial application,” Leira adds. “We are hopeful that this will result in a breakthrough in the treatment of stroke with the first effective cerebroprotectant.”
More realistic testing, more reliable results
These encouraging results were achieved in a new, more stringent type of preclinical trial, suggesting that uric acid therapy has the potential to improve outcomes in human stroke patients.
Preclinical trials use animal models of human disease as a starting point to test whether new treatments might work in patients. However, despite promising results, many of these therapies still fail when they progress to early-stage human trials.
“We were faced with a critical need to redesign the entire preclinical approach for stroke research,” said Francesca Bosetti, PhD, PharmD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH). “So, we developed a platform that applies clinical trial practices to animal studies and are now seeing a more stringent and successful screening of interventions. We hope to keep using this model to identify even more potential cerebroprotectants.”
The Stroke Preclinical Assessment Network (SPAN) is a unique testing platform developed by the NIH that allows for rigorous, controlled testing of drugs in preclinical (animal) studies. The SPAN platform closely mimics a human clinical trial; randomizing the animals to therapy or placebo with a rigorous testing strategy that minimizes biases, and accounts for age, sex, and other risk factors for stroke, like obesity and high blood pressure.
During a first round of SPAN testing, uric acid emerged as the only drug in the panel of six candidates to have a statistically significant effect in the prespecified behavioral primary outcome, minimizing the damage that can occur to brain tissue during a stroke or reperfusion.
The new study confirms that this effect persists when tested in both male and female rodents with comorbidities that mimic risk factors for stroke in people.
“Finding that uric acid’s cerebroprotection worked in all of these relevant biological situations makes the findings very exciting for the prospects of translating this approach to patients,” Leira says.
In addition to Leira and Chauhan, the research team also included first authors Rakesh Patel, PhD, and Mariia Kumskova, MD, in the UI Department of Internal Medicine, and Angel Chamorro, MD, PhD, who has appointments with UI Health Care and with University of Barcelona in Spain, and has pioneered the study of uric acid in stroke. The team also included colleagues from Icahn School of Medicine, Keck School of Medicine, University of Southern California, Medical College of Georgia, Johns Hopkins University, Harvard Medical School, University of Texas HSC, and Yale University School of Medicine.
The study was supported in part by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (U01NS113388).
(Editor’s note: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.)