NIH-Funded Research Targets Treatment for Brain Bleeding, Inflammation from Ruptured Aneurysms

About 30,000 people in the United States suffer a brain aneurysm rupture each year – about one every 18 minutes. Women – primarily between the ages of 40 and 60 — are more likely to suffer a brain aneurysm rupture, which are fatal in about 40 percent of cases in the U.S.

When a brain aneurysm ruptures, it is called a subarachnoid hemorrhage (SAH), which means a hemorrhage in the area between the brain and the skull. The resulting bleeding may extend into the brain itself.

Exploring cases of SAH and targeting treatment to prevent further brain inflammation and bleeding are key topics of research led by Khalid A. Hanafy, M.D., Ph.D., medical director of neurocritical care and director of research, at Marcus Neuroscience Institute, established at Boca Raton Regional Hospital, a part of Baptist Health.

Khalid A. Hanafy, M.D., Ph.D., medical director of neurocritical care and director of research, at Marcus Neuroscience Institute.

Dr. Hanafy is principal investigator of cutting-edge studies, including two currently funded by the U.S. National Institutes of Health (NIH) which have made recent progress toward developing advanced and personalized treatments for SAH patients and improve their survival rates and health outcomes, including the prevention of permanent cognitive impairments. His groundbreaking work in neuroinflammation has also been supported by American Heart Association, American Academy of Neurology, and Massachusetts Institute of Technology.

“Many of the advances so far have targeted the immediate treatment of aneurysms and the prevention of another rupture,” explains Dr. Hanafy. “But the brain can still suffer a massive state of inflammation and bleeding over the weeks following the initial treatment of the aneurysm. And we really have no treatments for any of that.”

In the most recent research development, Dr. Hanafy’s team was able to isolate the type of toll-like receptor 4 (TLR4) that does most of the damage following a ruptured aneurysm or SAH. TLR4 is a gene-encoded protein that is part of the natural immunity in humans.  There is increasing evidence of an involvement of TLRs in neurodegenerative diseases.

“The lack of microglial TLR4 was sufficient to prevent any cognitive dysfunction or neuronal injury after SAH,” the study states. “Thus, microglial TLR4 could be a potent therapeutic target to treat SAH-associated neuronal injury and protect against cognitive dysfunction.”

Microglia are a type of cell, responsible for eating debris, located throughout the brain and spinal cord. While the most current research was done in mice, future studies will determine what type of medication can eliminate the “microglial TLR4” influence on SAH patients, said Dr. Hanafy.

“When we took TLR4 off microglia cells, it wiped out the inflammation completely,” explains Dr. Hanafy. “We also conducted an experiment using clodronate liposome, a chemotherapeutic that depletes microglia. When given to mice, it eliminated inflammation.”

Previously, research has not really associated inflammation with stroke, he adds. “That’s a fairly new idea. Our study sheds some light on the causes of neuroinflammation for this patient population.”

A subarachnoid hemorrhage (SAH) can cause a range of life-threatening problems.

“When there’s still too much blood in the brain from SAH, it can cause all kinds of other serious issues, including heart and kidney problems — and it can cause a stroke,” he said. “All the blood that is coating the brain and all of the inflammation is mediated by microglial TLR4, and we need treatment for it. That’s what this research is for.”

Dr. Hanafy adds that ruptured aneurysms mostly affect relatively young women with few risk factors – high blood pressure and smoking primary among them.

“We are working on cutting-edge research that eventually give us new drugs derived from the mouse stroke model that we will bring into our patient population. And we’ll be sure that those new drugs are individualized and personalized to each patient.”