Every year in the United States, about 800,000 people experience a stroke. Many are left with neurological complications such as paralysis on one side of the body, speech and language problems, vision issues, behavioral changes, and memory loss.
Researchers at the University of Arizona Health Sciences aim to reduce these devastating effects by developing therapeutic treatments for acute stroke using a commonly prescribed class of drugs - cholesterol-reducing statins.
Using a $2.79 million grant from the National Institute of Neurological Disorders and Stroke (NINDS), a unit of the National Institutes of Health (NIH), Patrick T. Ronaldson, PhD, hopes to solve one of the main challenges when it comes to post-stroke treatments - the effective delivery of neuroprotective drugs, specifically statins, into the brain.
An associate profesor in the UArizona College of Medicine - Tucson's Department of Pharmacology, Dr. Ronaldson studies ischemic stroke, which occurs when blood supplied to the brain is obstructed by a clot. Current treatments, which focus on removing the blockage, are limited by time and treatment options. Many patients don't arrive at the hospital in time to undergo surgery or receive the one drug that is approved by the U.S. Food and Drug Administration for the treatment of ischemic stroke.
Research dating back to the mid-2000s offers clinical evidence that statins are effective in providing neuroprotection to stroke patients. When given to patients at high-risk for stroke, statins reduce the incidence of stroke. In post-stroke patients, statins decrease risk of recurrent strokes and improve functional outcomes.
"If you can get statins to the brain at effective concentrations, they actually are protective in the setting of stroke," Dr. Ronaldson said.
For years, the development of therapeutic drugs to treat ischemic stroke has been stopped, literally, by the blood-brain barrier, which is a network of blood vessels that run through the brain and protect it from toxins.
Because the blood-brain barrier plays a major role in preventing things from getting into the brain in the first place, Dr. Ronaldson said, it creates a challenge for doctors who need to get therapeutic drugs across the barrier to specific targets in the brain.
"There have been about 2,000 neuroprotective compounds that have been identified in pre-clinical studies over the past 20 years, and none of them have even made it to a Phase 3 clinical trial," Dr. Ronaldson said.
"Most of the research in drug discovery and stroke has focused on trying to identify something that works and then worrying about how to get it into the brain. We're taking something that we know works - statins - and figuring out exactly how to get it into the brain. If you appreciate that from day one, that's going to lead you to toward more effective therapies for stroke."
To that end, Dr. Ronaldson and his team are studying drug uptake transporters, which are proteins that carry drugs into tissues or organs, such as the brain, liver or kidneys. In prior research published in Molecular Pharmacology, he identified the specific family of transporters - organic anion transporting polypeptides (Oatps) - that can efficiently carry statins across the blood-brain barrier.
In the new study, Dr. Ronaldson's hypothesis is that Oatps can be targeted specifically for the purpose of delivering statins to the brain. He hopes to show that Oatp-mediated transport is the primary reason why statins work as a therapeutic treatment in stroke.
"This is the critical step in determining whether a statin works for stroke therapy," Dr. Ronaldson said, adding that some clinicians already give statins to stroke patients based on anecdotal evidence of improved outcomes.
"Our research will be able to inform treatment options for stroke so that clinicians can use that knowledge to try to make those treatments and statins more effective."
The research team also will be investigating ways to regulate Oatp transporters by manipulating the signaling pathways that control them. If researchers can control how and when the transporters work, they might be able to extend the narrow window of time that doctors have to effectively administer stroke treatments.
Eventually, Dr. Ronaldson would like to formulate statins that could be administered intravenously, which would allow medical professionals to deliver these drugs even earlier. Currently, statins are only sold in tablet form for oral delivery. That can be problematic for stroke patients, many of whom cannot swallow in the 24 hours immediately following a stroke.
Not only do we want to target a transporter and deliver the drug, but we want to control the playing field. If we can extend that therapeutic window and give first responders or emergency room clinicians a safe and effective tool that can reliably protect the brain, that's one of the best ways that we can make a contribution in terms of improving stroke therapy."
Patrick T. Ronaldson, PhD Department of Pharmacology, College of Medicine, University of Arizona
The study is supported by the NINDS/NIH under award number 2R01NS084941-06A1.
Abdullahi, W., et al. (2020) Functional Expression of Organic Anion Transporting Polypeptide 1a4 Is Regulated by Transforming Growth Factor-β/Activin Receptor-like Kinase 1 Signaling at the Blood-Brain Barrier. Molecular Pharmacology. doi.org/10.1124/mol.118.112912.