Tweaking the immune response shows potential for treating brain injuries

Brain Tissue
Hypoxia-ischemia (HI) results in tissue loss and injury in the brains of newborn mice. Two days after HI, in newborn mice with activated microglia, there is still extensive injury (LEFT image, arrow shows injuries). But in newborn mice that have been treated with the drug minocycline, which suppresses microglia activation, injuries appear far less severe (RIGHT image).

April 15, 2016
Adityarup “Rup” Chakravorty

Peter Ferrazzano, MD
Peter Ferrazzano, MD

Brain injuries caused by a lack of oxygen and blood flow affect many thousands of children every year, yet “we still don’t have effective treatments for them,” says Waisman researcher Peter Ferrazzano, MD.

Ferrazzano and his colleagues have been exploring tweaking the immune system to treat brain injuries caused by a lack of oxygen and nutrient-rich blood in children and adults. Mainly, they have focused on the inflammation that follows these kinds of brain injuries.

Complications during pregnancy or birth and traumatic events throughout childhood—near-drowning, choking episodes and strokes—can deprive the brain from getting vital oxygen and nutrient-rich blood, causing what is known as an ischemic injury. That can lead to long-term neurological issues, including learning disabilities and cerebral palsy, or even death.

“The inflammatory response after ischemic injuries is very complex—it may actually worsen the injury in some cases—but it’s increasingly clear that it can also have healing and neuroregenerative effects,” says Ferrazzano.

Ferrazzano has been focusing on a specific population of immune cells called microglia. Microglia are the first, and main, line of defense throughout the central nervous system, which includes the brain and the spinal cord.

“How microglia respond to different brain injuries can vary from patient to patient and depends on the severity, type and location of the injuries within the brain and—we’ve found—is also influenced by the age at which the injuries occur,” says Ferrazzano.

Understanding these age-related differences in how microglia respond to injury is vital if we are to develop potential therapies.

In a study published recently in the Journal of Neuroimmunology, Ferrazzano and colleagues used a drug to suppress how the microglia respond following brain injury in mice and tested how that would affect the recovery of newborn compared to more mature mice.

“The inflammation caused by microglia seems to be more vigorous in younger animals, so we hypothesized that suppressing this response would be more beneficial to these animals than older ones,” says Ferrazzano.

They were correct…partially. The drug did suppress the microglial response in both the newborn and older animals early after injury and protected the brain from injury. But when the researchers looked again at the brains of these mice two months after the ischemic injury, they found something unexpected.

“The newborn animals that initially looked protected went on to develop brain damage similar to that seen in animals that had not received the drug,” says Ferrazzano, “whereas the older animals continued to be protected from brain damage.”

The researchers also tested learning and memory skills in these mice. When treated with the microglia-suppressing drug, older mice that had suffered brain injury had intact memory and their learning skills were similar to mice that had suffered no brain damage.

“In contrast, in mice that had suffered brain injury as newborns, the drug had no protective effect on memory and learning,” says Ferrazzano.

According to Ferrazzano, these findings highlight the complexity of the inflammatory response and how important it is to understand the nuances of how microglia might react to injuries depending patient age.

“We are currently studying both the pro- and anti-inflammatory microglial response in the two age-groups of animals,” says Ferrazzano. By cataloging which genes get turned on or off in microglia following brain injury in newborn compared to older mice, Ferrazzano’s goal is to find the genes responsible for influencing which path the microglia take following ischemic injuries.

While medications to improve outcomes after brain injuries in children may be some time away, “understanding how age plays into the complexity of the microglial response is going to be very important as we take the next step in translating these findings into the clinic,” says Ferrazzano.

Study co-authors include Waisman researchers Ulas Cikla, Vishal Chanana, Douglas Kintner, Lucia Covert, Taylor Dewall, Alex Waldman, Paul Rowley and Pelin Cengiz. Ferrazzano and Cengiz are both associate professors in the Department of Pediatrics at the UW-Madison School of Medicine and Public Health.

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