Until recently the only treatment available for ischemic stroke was tissue plasminogen activator, or tPA, a protein that can dissolve blood clots if injected up to four and a half hours after stroke onset. Care has improved dramatically in the last few years as advances in thrombectomy—surgical clot removal—have allowed doctors to clear larger blockages and treat patients up to 24 hours after symptoms began.
Even after successful clot removal, however, the rush of blood back into the brain and the dying tissue left behind can lead to additional complications such as inflammation. To address this problem, researchers have been searching for more than 30 years for drugs that could protect the brain from damage after an ischemic stroke. More than a thousand compounds have been investigated in animal studies, and many have made it to clinical trials in people—with little success. “It’s been very disappointing for me and hundreds of other investigators that everything seems to work in animals and nothing works in humans,” says Susan Fagan, a clinical pharmacologist at The University of Georgia. “Neuroprotection is a hard nut to crack.”
But now, armed with guidelines for more rigorous animal studies and a better understanding of the processes that occur after stroke, researchers believe they are closer to finding compounds that can effectively reduce brain damage and lessen long-term effects on neurological function. Recent investigations in mice reveal that addressing the immune response—by inhibiting its harmful effects immediately after stroke or promoting its ability to aid recovery—may indeed lead to better outcomes.
A Targeted Attack
A collection of molecules called the “complement system” plays a key role in the body’s frontline defense against pathogens. When faced with microbial invaders, these molecules help immune cells fight off attackers and clear damaged cells and debris. But after a stroke this system can trigger harmful inflammatory processes that damage the brain.
Scientists have tried to address this, with little luck. One of the key problems is their approaches typically involved administering a therapeutic compound throughout the body. This dampened the intended effect and could leave patients susceptible to infections, says Ali Alawieh, an MD/PhD candidate in immunologist Steve Tomlinson’s lab at the Medical University of South Carolina.
Alawieh, Tomlinson and their colleagues developed a new method that would specifically target the injury site after an ischemic stroke. By combining Crry, a molecule that inhibits the complement system, and B4scFv, an antibody fragment engineered to identify stressed and injured cells, they were able to create a drug that could locate the stroke site and stop immune cells from attacking brain issue only there. The team induced strokes in mice and injected the combo (dubbed B4Crry) into their tails. Animals treated up to 24 hours after stroke had significantly less brain damage and fewer neurological problems, such as impaired movement and memory, than the untreated animals. The results appeared last month in Science Translational Medicine.