The complement system is a part of the innate immune system, and aids in the coordination of the immune response. It promotes inflammation, and in certain circumstances, such as the loss of blood supply to tissue, known as ischemia, it is actively harmful. Following a stroke, the complement system encourages the immune system to attack and destroy neurons and neural connections in the ischemic area, treating them as though they are dead or debris. A sizable fraction of those brain cells could in principle be salvaged if the blood supply is restored quickly enough, but the complement system actively sabotages this goal. Thus, researchers here propose a targeted interference in the complement system that could aid in limiting the functional damage of a stroke.

Reperfusion therapy, the gold standard for stroke treatment, helps restore blood flow after a stroke caused by a clot, preventing loss of brain tissue. However, only about 10% of stroke patients qualify, in part because of reperfusion therapy’s narrow treatment window. New research suggests that this therapy could be both safer and more effective for both motor and cognitive recovery if administered with a specialized compound that blocks the immune response. Reducing the immune response in the brain could be a strategy for improving cognitive recovery. It could also extend the treatment window for therapy, allowing stroke specialists to help many more stroke patients.

“With reperfusion therapy, we’re restoring the blood flow, which is necessary to save the tissue, but there is an ongoing inflammatory response by the immune system that is not targeted by reperfusion.” This could explain why, though mechanical reperfusion has a success rate of 90% in returning blood flow to the brain, only about 40% of treated patients recover enough motor and reasoning skills within three months to tend to their daily needs independently. Even those who do recover motor function can still struggle with cognitive challenges months later.

During a stroke, the oxygen and energy supply to the brain is cut off by a clot, causing brain tissue to become stressed and die rapidly. Just as it is with a cut to the knee, the immune system is activated to heal the wound, which includes clearing the dead tissue. A family of special immune proteins called complement proteins help to guide and promote this immune response in the damaged areas. These complement proteins flag both dead tissue and stressed brain cells for removal. The stressed brain cells are not yet dead, only damaged by lack of oxygen and energy, and thus salvageable tissue is destroyed by the immune system.

Researchers developed a complement protein blocker, named B4Crry, which acts only at the site of stroke injury. This compound blinds the complement proteins to the signals of stressed brain cells, saving the stressed tissue and reducing overall brain damage. In a mouse model of stroke, reperfusion therapy alone did improve recovery of coordinated movements such as walking. With the addition of B4Crry to treatment, coordinated movement improved even faster, with greater recovery seen as early as three days after the stroke. The improvements to learning and memory were even greater than those seen with motor functions. Reperfusion therapy alone was equal to no treatment at all for learning and memory recovery after stroke. However, when B4Crry was added to their treatments, mice had greatly improved cognitive recovery, making three times fewer errors on a learning and memory task.

After stroke, brain immune cells called microglia began eating the connections between stressed brain cells. Immune system complement proteins were marking these connections for destruction because they displayed the stressed cell signal. Without these connections, brain cells cannot communicate efficiently, and overall brain function decreases. B4Crry concealed the cells’ stress signals from the complement proteins and thereby saved the connections between neurons. Preserving connectivity improved learning and memory brain function after stroke.