Novel Therapy Inhibits Complement to Preserve Neurons and Reduce Inflammation After Stroke

Source: Medical University of South Carolina

Summary: Researchers have developed a novel therapy for ischemic (clot-caused) stroke that inhibits complement system and preserve neurons.

During an ischemic stroke, neurons in the perilesional area or penumbra, adjacent to the stroke core, are subjected to extreme stress. In response, perilesional neurons stop functioning and go into “survival mode.” The complement system is a component of both innate and adaptive immune responses and its dual role in both injury and recovery has made it a challenging target for potential stroke therapies. Researchers from the Medical University of South Carolina has shown in a preclinical model that it locally inhibits complement at and around the stroke core but does not inhibit the functioning of the complement system in other areas of the body. The study findings were published in the journal Science Translational Medicine.

 microglia phagocytosis of stressed neuron

Stylized illustration of microglia phagocytosis of a stressed neuron. (Blue – complement C3d, Orange – Microglia) Credit: Emma Vought, Medical University of South Carolina

The team conducted a series of experiments to clarify the role of complement in stroke since it contributes to both neurodegenerative and neuroregenerative processes. But, as sometimes happens, an unexpected finding led them to adjust their focus. While microglial phagocytosis (ingestion by microglia) of neurons has been previously described, the team’s experiments revealed that this process also occurs after stroke. They found that live but stressed neurons display danger-associated molecular patterns (DAMPs; also called neoepitopes) that trigger deposition of complement C3d on the outer cell membrane. The C3d tags the neuron for rapid clearance by inflammatory microglia. This ‘quick response’ mechanism helps explain the rapid loss of neurons observed in the perilesional area.

The first author, Ali Alawieh said, “This therapy allows more time to intervene and only requires a simple injection”, “It breaks the inflammatory response cycle and prevents chronic inflammation from occurring in the brain, which we know can continue for many years after a stroke.”

More information: A. Alawieh et al., “Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice,” Science Translational Medicine (2018). … scitranslmed.aao6459

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