Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions

• Neurological diseases increasing in incidence but lack effective treatment.
• Complement activation linked to the majority of neurological diseases.
• Inhibition of complement generally protective in neurological disease models.
• Therapies must balance protective and pathogenic sequela of complement activation.
• Complement inhibitors show promise as future candidates for clinical trials.

The recognition that complement proteins are abundantly present and can have pathological roles in neurological conditions offers broad scope for therapeutic intervention. Accordingly, an increasing number of experimental investigations have explored the potential of harnessing the unique activation pathways, proteases, receptors, complexes, and natural inhibitors of complement, to mitigate pathology in acute neurotrauma and chronic neurodegenerative diseases. Here, we review mechanisms of complement activation in the central nervous system (CNS), and explore the effects of complement inhibition in cerebral ischemic-reperfusion injury, traumatic brain injury, spinal cord injury, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease. We consider the challenges and opportunities arising from these studies. As complement therapies approach clinical translation, we provide perspectives on how promising complement-targeted therapeutics could become part of novel and effective future treatment options to improve outcomes in the initiation and progression stages of these debilitating CNS disorders.